Amide derivatives or salts thereof

ABSTRACT

Amide derivatives represented by general formula (I) or salts thereof wherein each symbol has the following meaning: ring B: an optionally substituted heteroaryl optionally fused with a benzene ring; X: a bond, lower alkylene or lower alkenylene optionally substituted by hydroxy or lower alkyl, carbonyl, or a group represented by -NH- (when X is lower alkylene optionally substituted by lower alkyl which may be bonded to the hydrogen atom bonded to a constituent carbon atom of ring B to form lower alkylene to thereby form a ring); A: a lower alkylene or a group represented by -(lower alkylene)-O-; R1a and R1b: the same or different and each hydrogen or lower alkyl; R2: hydrogen or halogeno; and Z: nitrogen or a group represented by =CH-. The compounds are useful as a diabetes remedy which not only functions to both accelerate the secretion of insulin and enhance insulin sensitivity but has an antiobestic action and an antihyperlipemic action based on its selective stimulative action on a beta3 receptor.

TECHNICAL FIELD

The present invention relates to pharmaceuticals and, more particularly,it relates to novel amide derivatives or salts thereof and also totherapeutic agents for diabetes mellitus containing them as effectivecomponents.

BACKGROUND OF THE INVENTION

Diabetes mellitus is a disease accompanied by continuous hyperglycemicstate and is said to be resulted by action of many environmental factorsand genetic factors. The main controlling factor for blood sugar isinsulin, and it has been known that hyperglycemia is resulted bydeficiency of insulin or by excess of factors which inhibit its action(such as genetic cause, lack of exercise, obesity and stress).

Diabetes mellitus is classified into two main types. One isinsulin-dependent diabetes mellitus (IDDM) caused by a lowering ofinsulin-secreting function of pancreas due to autoimmune diseases, andanother is non-insulin-dependent diabetes mellitus (NIDDM), caused by alowering of insulin-secreting function of pancrease due to pancreaticfatigue accompanied by continuous high insulin secretion. 95% or more ofdiabetic patients in Japan are said to suffer from NIDDM, and anincrease in the patients due to a change in daily life style is becominga problem.

As to the therapy of diabetes mellitus, dietetic treatment, therapeuticexercise and remedy of obesity are mainly conducted in mild cases while,when the disease progresses, oral antidiabetic drugs (for example,insulin secretion promoters such as sulfonylurea compounds and insulinsensitivity potentiators which potentiate the sensitivity of insulin)are administered. In severe cases, an insulin preparation isadministered. However, there has been a brisk demand for creation of thedrugs whereby higher control for blood sugar is possible, anddevelopment of antidiabetic drugs having a new mechanism and having highusefulness has been demanded.

U.S. Pat. Nos. 4,396,627 and 4,478,849 describe phenylethanolaminederivatives and disclose that those compounds are useful as drugs forobesity and for hyperglycemia. Action of those compounds is reported tobe due to a stimulating action to β₃-receptors. Incidentally, it hasbeen known that β-adrenaline receptors are classified into β₁, β₂ and β₃subtypes, that stimulation of β₁-receptor causes an increase in heartrate, that stimulation of β₂-receptor stimulates decomposition ofglycogen in muscles, whereby synthesis of glycogen is inhibited, causingan action such as muscular tremor, and that stimulation of β₃-receptorshows an anti-obesity and an anti-hyperglycemia action (such as decreasein triglyceride, decrease in cholesterol and increase inHDL-cholesterol).

However, those β₃-agonists also have actions caused by stimulation ofβ₁- and β₂-receptors such as increase in heart rate and muscular tremor,and they have a problem in terms of side effects.

Recently, it was ascertained that β-receptors have differences tospecies, and it has been reported that even compounds having beenconfirmed to have a β₃-receptor selectivity in rodential animals such asrats show an action due to stimulating action to β₁- and β₂-receptors inhuman being. In view of the above, investigations for compounds having astimulating action which is selective to β₃-receptor in human being havebeen conducted recently using human cells or cells where human receptorsare expressed. For example, WO 95/29159 describes substitutedsulfonamide derivatives represented by the formula set forth below anddiscloses that due to their selective stimulating action to β₃-receptorsin human being, they are useful against obesity, hyperglycemia, etc.However, this patent does not specifically disclose an insulin secretionpromoting action and an insulin sensitivity potentiating action of thosecompounds.

(In the formula, the symbols should be referred to in the specificationof this patent.)

As such, there has been still a demand for creation of therapeuticagents for diabetes mellitus of a new type which have a highly clinicalusefulness.

DISCLOSURE OF THE INVENTION

The present inventors have conducted an intensive investigation oncompounds having both an insulin secretion promoting action and aninsulin sensitivity potentiating action and found that novel amidederivatives show both a good insulin secretion promoting action and agood insulin sensitivity potentiating action and furthermore show aselective stimulating action to β₃-receptors, leading to accomplishmentof the present invention.

That is, the present invention relates to an amide derivativerepresented by the general formula (I) set forth below or a salt thereofthat is useful for the therapy of diabetes mellitus, having both aninsulin secretion promoting action and an insulin sensitivitypotentiating action and further having anti-obesity andanti-hyperlipemia actions due to a selective stimulating action toβ₃-receptors. The present invention also relates to a pharmaceuticalagent, particularly to a therapeutic agent for diabetes mellituscontaining the amide derivative or the salt thereof as an effectiveingredient.

(In the formula, each of the symbols means as follows:

ring B: a heteroaryl group which may be substituted and may be fusedwith a benzene ring;

X: a bond, lower alkylene or alkenylene which may be substituted withhydroxy or a lower alkyl group, carbonyl, or a group represented by —NH—(when X is a lower alkylene group which may be substituted with a loweralkyl group, the hydrogen atoms bonded to the carbon atom constitutingthe ring B may form a lower alkylene group together with the lower alkylgroup so that a ring is formed);

A: lower alkylene or a group represented by -lower alkylene-O—;

R^(1a), R^(1b): they may be the same or different and each is a hydrogenatom or a lower alkyl group;

R²: a hydrogen atom or a halogen atom; and

Z: a nitrogen atom or a group represented by ═CH—.)

The compound of the general formula (I) is further illustrated asfollows.

In the definitions used in the general formula in this specification,the term “lower” means a linear or branched hydrocarbon chain havingfrom 1 to 6 carbon atoms unless otherwise specified.

Specific examples of the “lower alkyl group” are methyl, ethyl, andlinear or branched propyl, butyl, pentyl and hexyl, preferably an alkylhaving from 1 to 4 carbon atoms, and particularly preferably methyl,ethyl, propyl and isopropyl.

Examples of the “lower alkylene group” is a divalent group obtained byremoving an arbitrary hydrogen atom(s) from the above “lower alkylgroup”, preferably an alkylene group having from 1 to 4 carbon atoms,and particularly preferably methylene, ethylene, propylene and butylene.Examples of the “lower alkenylene group” are vinylene, propenylene,butenylene, pentenylene and hexenylene groups.

The “heteroaryl group which may be fused with a benzene ring” in the“heteroaryl group which may be substituted and may be fused with abenzene ring” means a ring group where a benzene ring is fused with aheteroaryl group as mentioned later or a non-fused heteroaryl group.

Specific examples of the “ring group where the benzene ring is fusedwith a heteroaryl group” are fused-ring heteroaryl groups such asquinolyl, isoquinolyl, quinazolinyl, quinolidinyl, quinoxalinyl,cinnolinyl, benzimidazolyl, imidazopyridyl, benzofuranyl,benzoisoxazolyl, benzoxazolyl, benzothiazolyl, oxazolopyridyl,isothiazolopyridyl, benzothienyl, etc.; and oxo-added rings such asoxobenzofurayl, etc.

Examples of the “heteroaryl group” are monocyclic heteroaryl groups suchas furyl, thienyl, pyrrolyl, imidazolyl, thiazolyl, pyrazolyl,isothiazolyl, isoxazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl,thiadiazolyl, triazolyl, tetrazolyl, etc.; and bicyclic heteroarylgroups such as naphthylidinyl, pyridopyrimidinyl, etc.

The substituent in the “heteroaryl group which may be substituted andmay be fused with a benzene ring” may be any group which can be usuallysubstituted in this ring group. Preferred examples are a halogen atomand lower alkyl, lower alkenyl, lower alkynyl, hydroxy, sulfanyl,halogeno lower alkyl, lower alkyl-O—, lower alkyl-S—, lower alkyl-O—CO—,carboxy, sulfonyl, sulfinyl, lower alkyl-SO—, lower alkyl-SO₂—, loweralkyl-CO—, lower alkyl-CO—O—, carbamoyl, lower alkyl-NH—CO—, di-loweralkyl-N—CO—, nitro, cyano, amino, guanidino, lower alkyl-CO—NH—, loweralkyl-SO₂—NH—, lower alkyl-NH—, di-lower alkyl-N—, —O-lower alkylene-O—,etc. These substituents may further be substituted with a substituentsuch as an aryl group, a heteroaryl group, a halogen atom, hydroxy,sulfanyl, halogeno lower alkyl, lower alkyl-O—, lower alkyl-S—, loweralkyl-O—CO—, carboxy, sulfonyl, sulfinyl, lower alkyl-SO—, loweralkyl-SO₂—, lower alkyl-CO—, lower alkyl-CO—O—, carbamoyl, loweralkyl-NH—CO—, di-lower alkyl-N—CO—, nitro, cyano, amino, guanidino,lower alkyl-CO—NH—, lower alkyl-SO₂—NH—, lower alkyl-NH—, di-loweralkyl-N—, etc. These substituents such as an aryl group, a heteroarylgroup, etc. may further be substituted with a halogen atom, etc.

The “lower alkenyl group” is a linear or branched alkenyl group having 2to 6 carbon atoms, and its specific examples are vinyl, propenyl,butenyl, pentenyl and hexenyl groups.

The “lower alkynyl group” is a linear or branched alkynyl group having 2to 6 carbon atoms, and its specific examples are ethynyl, propynyl,butynyl, pentynyl and hexynyl.

The “halogen atom” means a fluorine atom, a chlorine atom, a bromineatom or an iodine atom, and the “halogeno lower alkyl group” means agroup where an arbitrary hydrogen atom or atoms in the above-mentionedalkyl group is/are substituted with a halogen atom or atoms.

The case when X is a bond means that a carbon atom of the —CO— group isdirectly bonded to the ring B.

The compound (I) of the present invention has at least one asymmetriccarbon atom and therefore, there are optical isomers such as(R)-compounds, (S)-compounds, etc., racemates, diastereomers, etc. Thepresent invention includes all and each of isolated isomers and mixturesthereof. The present invention also includes hydrates, solvates (such asthose with ethanol) and polymorphic substances of the compound (I).

The compound (I) of the present invention may form a salt with an acid.Examples of the salt are acid addition salts with mineral acids such ashydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid,nitric acid, phosphoric acid, etc.; and those with organic acids such asformic acid, acetic acid, propionic acid, oxalic acid, malonic acid,succinic acid, fumaric aid, maleic acid, lactic acid, malic acid, citricacid, tartaric acid, carbonic acid, picric acid, methanesulfonic acid,ethanesulfonic acid, glutamic acid, etc.

Manufacturing Method

The compound of the present invention or the salt thereof may bemanufactured by application of various synthetic methods utilizing thecharacteristics of its fundamental skeleton or type of the substituent.Representative manufacturing methods are illustrated as hereunder.

First Manufacturing Method

(In the formulae, R^(1a), R^(1b), R², A, B, X and Z have the samemeanings as defined already; R^(a) is a protective group for amino; andY¹ is a leaving group, and more specifically hydroxy, lower alkoxy orhalide.)

In this method, the compound (II) and the compound (III) are subjectedto amidation, and the protective group is then removed therefrom tosynthesize the compound (I) of the present invention.

The amidation in this manufacturing method can be conducted by customarymanners.

The solvent may vary depending upon Y¹ of the compound (III) and mostly,an inert solvent or an alcoholic solvent (such as isopropanol, etc.) maybe applied.

When Y¹ is a hydroxy group, a method where the reaction is conducted inthe above-mentioned solvent in the presence of a condensing agent may beapplied. Examples of the condensing agent areN,N′-dicyclohexylcarbodiimide (DCC),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI),1,1′-carbonyldiimidazole (CDI), diphenylphosphoryl azide (DPPA),diethylphosphoryl cyanide (DEPC), etc.

When Y¹ is lower alkoxy, a method where the reaction is conducted underheating or refluxing as it is or in the above-mentioned inert solventmay be applied.

When Y¹ is halide, a method where the reaction is conducted in theabove-mentioned inert solvent in the presence of a base may be applied.

Examples of the inert solvent are dimethylformamide (DMF),dimethylacetamide, tetrachloroethane, dichloromethane, dichloroethane,chloroform, carbon tetrachloride, tetrahydrofuran, dioxane,dimethoxyethane, ethyl acetate, benzene, toluene, xylene, acetonitrile,dimethyl sulfoxide, etc., and mixed solvents thereof, and they may beappropriately selected depending upon each reaction condition. Examplesof the base are inorganic bases such as sodium hydroxide, potassiumhydroxide, sodium carbonate, potassium carbonate, etc.; and organicbases such as N-methylmorpholine, triethylamine, diisopropylethylamine,pyridine, etc.

The protective group of the amino represented by R^(a) means aprotective group which is commonly used for amino by those skilled inthe art, and its representative examples are acyl such as formyl,acetyl, propionyl, methoxyacetyl, methoxypropionyl, benzoyl,thienylacetyl, thiazolylacetyl, tetrazolylacetyl, thiazolylglyoxyloyl,thienylglyoxyloyl, etc.; lower alkoxycarbonyl such as methoxycarbonyl,ethoxycarbonyl, tert-butoxycarbonyl, etc.; aralkyloxy-carbonyl such asbenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, etc.; lower alkanesulfonylsuch as methanesulfonyl, ethanesulfonyl, etc.; aralkyl such as benzyl,p-nitrobenzyl, benzhydryl, trityl, etc.; tri-(lower alkyl)silyl such astrimethylsilyl, etc.; and the like.

Removal of the protective group in this manufacturing method may beconducted by customary manners. For example, the protective group foramino represented by R^(a) may be easily removed, for example, by i) amethod where in case that the protective group is benzhydryl,p-methoxybenzyl, trityl, tert-butoxycarbonyl, formyl, etc., treatmentwith an acid such as formic acid, trifluoroacetic acid, atrifluoroacetic acid-anisole mixed solution, a hydrobromic acid-aceticacid mixed solution, a hydrochloric acid-dioxane mixed solution, etc. isconducted; ii) a method where in case that the protective group isbenzyl, p-nitrobenzyl, benzhydryl, trityl, etc., a catalytic reductionmethod using palladium-carbon or palladium hydroxide-carbon isconducted; and iii) a method where in case that the protective group isa tri-(lower alkyl) silyl or the like, treatment with water, fluorideanion (e.g., tetra-n-butylammonium fluoride, sodium fluoride, potassiumfluoride, hydrofluoric acid), etc. is conducted.

Second Manufacturing Method

(In the formulae, R^(1a), R^(1b), R², A, B, X and Z have the samemeanings as defined already.)

In this manufacturing method, the compound (IV) is reacted with thecompound (V) to give the compound (I) of the present invention.

The amine compound (IV) and the compound (V) are reacted under heatingor refluxing for 1 to 24 hours as they are or in an inert solvent, togive the compound (I) of the present invention.

Examples of the inert solvent are acetonitrile, tetrahydrofuran,2-butanone, dimethyl sulfoxide and N-methylpyrrolidone. In the reaction,a base such as sodium bicarbonate, potassium carbonate ordiisopropylethylamine may be added to the reaction mixture.

Incidentally, in the above manufacturing methods, it is possible topurify the resulting substance by removing undesired by-products bymeans of recrystallization, pulverization, preparative thin layerchromatography, silica gel flash chromatography (as described in W. C.Still, et al., J. Org. Chem., 43, 2923 (1978)), medium-pressure liquidchromatography and HPLC. The compound produced through HPLC can beisolated as a corresponding salt.

The starting material used in the above-mentioned manufacturing methodsmay be easily manufactured by the methods which are known to thoseskilled in the art. One of the representative methods is shown ashereunder.

Manufacturing Method for the Starting Compound (II)

(In the formulae, R^(1a), R^(1b), R², R^(a), A and Z have the samemeanings as defined already; R^(b) is a hydrogen atom or anaralkyl-based protective group for amino; and R^(c) is epoxy,2-haloacetyl or 1-carboxymethan-1-ol.)

This manufacturing method is composed of from step (a) to step (c) inwhich the step (a) is a step where the compound (VI) is reacted with thecompound (VII), followed by reduction reaction to give the compound(VIIIa) depending upon the type of R^(c),; the step (b) is a step whereprotection is conducted when R^(b) of the compound (VIIIa) is a hydrogenatom; and the step (c) is a step where nitro is reduced to amino to givethe compound (II).

Examples of the aralkyl-based protective group for amino used in thismanufacturing method are benzyl, p-nitrobenzyl, benzhydryl, etc.

Step (a)

Illustration is made for the following three cases.

1) When R^(c) is epoxy, the compound (VI) may be reacted with thecompound (VII) by the same manner as in the above-mentioned secondmanufacturing method. Reaction conditions such as reaction temperature,solvent, etc. are the same as well.

2) When R^(c) is 2-haloacetyl, the compound (VI) is reacted with thecompound (VII) in the presence of a base, followed by reduction reactionto prepare the compound (VIIIa). The base is the same as that mentionedin the first manufacturing method. The reduction reaction may beconducted in the above-mentioned inert solvent or in a solvent of analcohol type with stirring in the presence of a reducing agent. Examplesof the reducing agent are sodium borohydride, sodium cyanoborohydride,lithium aluminum hydride, borane, etc.

3) When R^(c) is 1-carboxymethan-1-ol, the compound (VI) is reacted withthe compound (VII) in the presence of a condensing agent, followed byreduction reaction in the same manner as in 2) to prepare the compound(VIIIa). The condensing agent is the same as that mentioned in the firstmanufacturing method.

Step (b):

When R^(b) in the compound (VIIIa) is a hydrogen atom, the amino groupis protected by customary manners using di-tert-butyl dicarbonate, etc.,to prepare the compound (VIIIa).

Step (c):

A method for the reduction of nitro to amino may be conducted bycustomary manners such as metallic reduction using iron, zinc, etc. andcatalytic reduction using a catalyst such as palladium-carbon, palladiumhydroxide-carbon, Raney nickel, etc. R^(a) becomes a hydrogen atomdepending upon the reduction conditions, but it may be protected againby customary manners.

Manufacturing Method for Starting Compound (IV)

(In the formulae, R^(1a), R^(1b), R^(b), A, B, X and Y¹ have the samemeanings as defined already.)

This reaction is a reaction where the compound (IX) and the compound(III) are subjected to amidation reaction to give a compound (IVa) and,when R^(b) is a protective group for amino, the protective group isremoved to give a compound (IV). The amidation reaction can be conductedby the same manner as in the above-mentioned first manufacturing method,and the reaction conditions such as reaction temperature, solvent, etc.are the same as well.

This reaction is a reaction where the compound (X) and the compound(III) are subjected to amidation reaction and then to reduction reactionto give a compound (IVb). The amidation reaction can be conducted by thesame manner as in the above-mentioned first manufacturing method, andthe reaction conditions such as reaction temperature, solvent, etc. arethe same as well. In the reduction reaction, the above-mentionedcatalytic reduction, or a method where reduction is conducted usingsodium borohydride in the presence of cobalt chloride, may be applied.

With regard to other compounds such as the compound (III), the compound(V), the compound (VI), and the compound (VII), those which areavailable in the market or are appropriately synthesized by knownmethods (such as N-alkylation reaction, cyclization reaction, hydrolysisreaction, etc.) from the commercially available compounds may be used.

The compound (I) of the present invention which is manufactured as suchis isolated and purified as a free compound, a salt thereof obtained bymeans of salt formation by customary manners, a hydrate, a solvate withvarious solvents such as ethanol, etc., or polymorphic crystals, etc.The isolation and purification may be conducted by applying commonchemical operations such as extraction, concentration, evaporation,crystallization, filtration, recrystallization, various chromatographicmethods, etc.

Various isomers may be isolated by customary manners utilizing thephysico-chemical differences between the isomers. For example, theracemate can be converted to stereochemically pure isomers by commonracemic resolution (such as a method where the racemate is changed todiastereomer salts with usual optically active acid (for example,tartaric acid), followed by optical resolution, and the like).Incidentally, a mixture of diastereomers may be separated by customarymethod such as fractional crystallizaiton or chromatography, etc. In thecase of an optically active compound, it may be manufactured startingfrom an appropriate optically active material.

Industrial Applicability

The phenethanol derivative of the present invention represented by thegeneral formula (I) or the salt thereof has both an insulin secretionpromoting action and an insulin sensitivity potentiating action and alsohas a selective β₃-receptor stimulating action, so that it is useful asa therapeutic agent for diabetes mellitus.

As confirmed by a glucose tolerance test and a hypoglycemic test ininsulin-resisting model animals as described later, the compound of thepresent invention has both a good insulin secretion promoting action anda good insulin sensitivity potentiating action, so that its usefulnessin diabetes mellitus is expected. Although the β₃-receptor stimulatingaction may have a possibility of participating in expression of theinsulin secretion promoting action and the insulin sensitivitypotentiating action, other mechanism might also possibly participatetherein, and the details thereof have been still unknown yet. Theβ₃-receptor stimulating action of the compound of the present inventionis selective to β₃-receptors in human being. It has been known that thestimulation of β₃-receptor stimulates decomposition of fat(decomposition of the fat tissue triglyceride into glycerol and freefatty acid), whereby a disappearance of fat mass is promoted. Therefore,the compound of the present invention has an anti-obesity action and ananti-hyperlipemia action (such as triglyceride lowering action,cholesterol lowering action and HDL cholesterol increasing action) andis useful as a preventive and therapeutic agent for obesity andhyperlipemia (such as hypertriglyceridemia, hypercholesterolemia andhypo-HDL-lipoproteinemia). Those diseases have been known as animusfactors in diabetes mellitus, and amelioration of those diseases isuseful for prevention and therapy of diabetes mellitus as well.

The compound of the present invention is also useful as a preventive andtherapeutic agent for other diseases where the improvement of symptomcan be achieved by reducing the symptoms of obesity and hyperlipemiasuch as ischemic coronary diseases such as arteriosclerosis, myocardialinfarction, angina pectoris, etc. cerebral arteriosclerosis such ascerebral infarction, etc., or aneurysm, etc.

Further, the selective β₃-receptor stimulating action of the compound ofthe present invention is useful for prevention and therapy of s severaldiseases which have been reported to be improved by the stimulation ofβ₃-receptor. Examples of those diseases are shown as follows.

It has been mentioned that the β₃-receptor mediates the motility ofnon-sphincteral smooth muscle contraction, and because it is believedthat the selective β₃-receptor stimulating action assists thepharmacological control of intestinal motility without being accompaniedby cardiovascular action, the compound of the present invention has apossibility of being useful in therapy of the diseases caused byabnormal intestinal motility such as various gastrointestinal diseasesincluding irritable colon syndrome. It is also useful as the therapy forpeptic ulcer, esophagitis, gastritis and duodenitis (including thatinduced by H. pylori), enterelcosis (such as inflammatory intestinaldiseases, ulcerative colitis, clonal disease and proctitis).

It is further shown that the β₃-receptor affects the inhibition ofrelease of neuropeptide of some sensory fibers in lung. The sensorynerve plays an important role in neurogenic inflammation of respiratorytract including cough, and therefore, the specific β₃-agonist of thepresent invention is useful in the therapy of neurogenic inflammationand in addition, has little action to cariopulmonary system.

Moreover, the β₃-adrenaline receptor is capable of resulting in aselective antidepressant action due to stimulation of the β₃-receptor inbrain, and accordingly, the compound of the present invention has apossibility of being useful as an antidepressant.

The action of the compound of the present invention has been ascertainedto be selective to β₃-receptors as a result of experiments using cellsexpressing human type receptors, and the adverse action caused by otherβ₃-receptor stimulation is low or none.

Effects of the compound of the present invention have been ascertainedby the following tests.

1. Hypoglycemic Test in kk Mice (insulin-resisting model; Obesity andHyperglycemia)

Male kk mice (blood sugar level: not lower than 200 mg/dl) weresubjected to a measurement of blood sugar level under feeding and thenrandomly classified into groups. The drug to be tested was compulsorilyadministered orally or subcutaneously once daily for four days, and theblood sugar level after 15 to 18 hours from the final administration wascompared with that before the administration (n=6). The blood wascollected from a tail vein of the mice using a glass capillary(previously treated with heparin), the protein was removed therefrom,and the amount of glucose in the supernatant liquid (mg/dl) was measuredby calorimetric determination by means of a glucose oxidase method.Further, a dose at which the blood sugar level was lowered by 30% ascompared with that before the administration with the drug to be testedwas expressed as an ED₃₀ value.

As a result, the compound of the present invention significantly loweredthe blood sugar level as compared with that before the administrationwith the drug to be tested in both cases of oral and subcutaneousadministrations. In particular, some of the compounds of the presentinvention exhibited a strong activity so that the ED₃₀ value in the oraladministration was 3 mg/kg/day or less. On the other hand, in theabove-referenced WO 95/29159, the compound of Example 90 had an ED₃₀value of 30 mg/kg/day or more, and the compound of Example 92 had anED₃₀ value of 30 mg/kg/day. From this fact, it has become clear that thecompounds of the present invention have a superior potentiating actionto insulin sensitivity as compared with those of the above-referenced WO95/29159.

2. Glucose Tolerance Test in Normal Rats

Male rats of SD strain of seven weeks age were fasted for a whole dayand night, then randomly classified into groups and subjected to an oralglucose tolerance test (OGTT) (n+4). The compound to be tested wasadministered orally or subcutaneously at 30 minutes beforeadministration of glucose (2 g/kg by oral administration). The blood wascollected from an abdominal aorta using a heparin-treated glass syringefrom the rats which were anesthetized with pentobarbital (65 mg/kg), theprotein was removed therefrom, and the amount of glucose in thesupernatant liquid (mg/dl) was measured by colorimetric determination bymeans of a glucose oxidase method. The insulin value in blood wasdetermined by measuring the amount of insulin in plasma (ng/ml) by meansof radioimmunoassay (RIA).

As a result, in a group where the compound of the present invention wasadministered orally or subcutaneously, a significant increase in theinsulin value in blood was observed as compared with the group to whichno drug was given. An increase in the sugar blood level afteradministration of glucose was significantly inhibited as well. Fromthose results, it is apparent that the compound of the present inventionhas a good insulin secretion promoting action and a good hyperglycemiainhibiting action.

3. Stimulating Test to Human β₃-, β₂- and β₁-receptors

Human β₃-stimulating action was investigated using an SK-N-MC cellsystem (cells in which human β₃-receptor and human β₁-receptor werepermanently expressed were purchased) while human β₂- and β₁-stimulatingactions were investigated using a CHO cell system (cells in which eachof human β₂- and β₁-receptors was compulsorily expressed werepurchased). Stimulating action of the compound (10⁻¹⁰ to 10⁻⁴ M) wereinvestigated by incubating 10⁵ cells/well of each of the cells on a24-well plate and checking under a subconfluent state after two daysusing a producing activity of cyclic AMP (cAMP) as an index.Incidentally, the human β₃-stimulating action was investigated in thepresence of a β₁-receptor blocker (CGP20712A, 10⁻⁶ M). Amount ofproduction of cAMP in each cell (pmol/ml) was measured by an RIA methodusing ¹²⁵I-cAMP. Intensity of action of each compound was compared bycalculating the pD2 value and the maximum activity (I.A. (%) where themaximum reaction of 10⁻⁶ M isoproterenol was defined as 100%) from theresulting dose-reaction curve.

As a result, it has been ascertained that the compound of the presentinvention has a selective stimulating action to human β₃-receptor.

A pharmaceutical composition containing one or more of the compound ofthe present invention or the salt thereof as an effective ingredient isprepared using common pharmaceutically acceptable vehicles.Administration of the pharmaceutical composition according to thepresent invention may be either by oral administration or by parenteraladministration by, for example, injection, suppository, subcutaneousagent, inhaling agent or intracystic infusion.

The dose may be appropriately decided depending upon each particularcase while taking into consideration symptom, age, sex, etc. of thepatient but usually, is around 0.01 mg/kg to 100 mg/kg per day foradults in the case of oral administration, and that is administered at atime or by dividing into 2 to 4 times a day. When intravenous injectionis conducted depending upon the symptom, the dose is usually around0.001 mg/kg to 10 mg/kg per day for adults, and that is administered ata time or by dividing into two or more times a day.

With regard to a vehicle for the preparation, nontoxic solid or liquidsubstances for pharmaceuticals may be used.

Examples of the solid composition for use by means of oraladministration according to the present invention are tablets, pills,capsules, diluted powder and granules. In such a solid composition, oneor more active substances are mixed with at least one inert excipientsuch as lactose, mannitol, glucose, hydroxypropyl cellulose,microcrystalline cellulose, starch, polyvinylpyrrolidone, agar, pectin,magnesium metasilicate aluminate and magnesium aluminate. Thecomposition may also contain additives other than the inert excipientsuch as lubricants such as magnesium stearate; disintegrants such ascalcium cellulose glycolate; stabilizers such as lactose; and auxiliarysolubilizers such as glutamic acid or aspartic acid by customarymanners. Tablets and pills may, if necessary, be coated with sugar coatsuch as sucrose, gelatin, hydroxypropyl cellulose, hydroxypropylmethylcellulose phthalate, etc., or with film of gastric or enteric coatingsubstances.

The liquid composition for oral administration includes pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups and elixirs andcontains commonly used inert excipients such as purified water orethanol. In addition to the inert excipient, the composition may furthercontain auxiliary agents such as moisturizing or suspending agents,sweeteners, tasting agents, aromatic agents and antiseptic agents. Theinjection for parenteral administration includes aseptic aqueous ornon-aqueous solutions, suspensions and emulsions. The non-aqueoussolutions and suspensions include, for example, distilled water forinjection and a physiological saline solution. Examples of the solventfor non-aqueous solution and suspension are propylene glycol;polyethylene glycol; plant oils such as cacao butter, olive oil andsesame oil; alcohols such as ethanol; gum arabic; and Polysolvate 80(trade name). Such a composition may further contain auxiliary agentssuch as isotonizing agents; antiseptic agents; moisturizing agents;emulsifiers; dispersing agents; stabilizers such as lactose; andauxiliary solubilizers such as glutamic acid and aspartic acid). Thesemay be sterilized, for example, by filtration passing through abacteria-preserving filter or by compounding of or irradiation with abactericide. These may also be used by manufacturing a sterile solidcomposition, followed by dissolving in sterile water or a sterilesolvent for injection before use.

Best Mode for Carrying Out the Invention

The present invention is further illustrated by way of Examples ashereunder. Compounds of the present invention are not limited to thosementioned in the following Examples but cover all of the compoundsrepresented by the above general formula (I), salts thereof, hydratesthereof, geometric and optical isomers thereof and polymorphic formsthereof. Incidentally, the case where the material which is used in thepresent invention is novel is illustrated by way of the followingReferential Example.

REFERENTIAL EXAMPLE 1

To a mixed solution of ethyl acetate and a 1N aqueous solution of sodiumhydroxide was added 25.2 g of 4-nitrophenyl ethylamine hydrochloride,and the mixture was vigorously stirred. The organic layer was dried overanhydrous magnesium sulfate, and the solvent was evaporated. To theresulting residue were added 100 ml of 2-propanol and 15.0 g of(R)-styrene oxide successively, and the reaction mixture was heated toreflux for 12 hours. The solvent was evaporated in vacuo, and theresidue was purified by silica gel column chromatography (eluent:chloroform/methanol=100/1→10/1) The resulting residue was againsubjected to silica gel column chromatography (eluent: hexane/ethylacetate/triethylamine=1/5/trace) to give 8.05 g of(R)-1-phenyl-2-[[2-(4-nitrophenyl) ethyl]amino]ethanol.

REFERENTIAL EXAMPLE 2

A solution of 8.02 g of(R)-1-phenyl-2-[[2-(4-nitrophenyl)ethyl]amino]ethanol and 6.30 g ofdi-tert-butyl dicarbonate in 80 ml of tetrahydrofuran was stirred for 12hours at room temperature. The residue obtained by evaporation of thesolvent was purified by silica gel column chromatography (eluent:hexane/ethyl acetate=3/1) to give 10.8 g of tert-butyl(R)-N-(2-hydroxy-2-phenylethyl)-N-[2-(4-nitro-phenyl)ethyl]carbamate.

REFERENTIAL EXAMPLE 3

To a solution of tert-butyl(R)-N-(2-hydroxy-2-phenylethyl)-N-[2-(4-nitrophenyl)ethyl]carbamate in200 ml of ethanol was added 1.03 g of 10% palladium-carbon and themixture was stirred for two hours at room temperature in a hydrogenatmosphere under atmospheric pressure. Insoluble matters were removedusing Celite, and the filtrate was concentrated in vacuo to give 9.54 gof tert-butyl(R)-N-[2-(4-aminophenyl)-N-(2-hydroxy-2-phenylethyl)ethyl]-carbamate.

REFERENTIAL EXAMPLE 4

To a solution of 448 mg of tert-butyl(R)-N-[2-(4-aminophenyl)-N-(2-hydroxy-2-phenylethyl)ethyl]carbamate and330 mg of triethylamine in 4 ml of chloroform was added 146 mg of2-pyridinecarbonyl chloride. The reaction solution was stirred at roomtemperature for two hours, and the solvent was evaporated in vacuo. Theresidue was diluted with chloroform, and the organic layer was washedwith a saturated aqueous solution of sodium hydrogen carbonate and driedover anhydrous magnesium sulfate. The residue obtained by evaporatingthe solvent in vacuo was purified by silica gel column chromatography(eluent: hexane/ethyl acetate=1/3) to give 321 mg of tert-butyl(R)-N-(2-hydroxy-2-phenylethyl)-N-[2-[4-[(2-pyridinecarbonyl)amino]phenyl]ethyl]carbamate.

REFERENTIAL EXAMPLE 5

To a solution of 377 mg of tert-butyl(R)-N-[2-(4-aminophenyl)-N-(2-hydroxy-2-phenylethyl)ethyl]carbamate in10 ml of tetrahydrofuran were added 203 mg of1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, 143 mg of1-hydroxybenzotriazole and 202 mg of 8-quinolinecarboxylic acidsuccessively. The reaction solution was stirred at room temperature for18.5 hours, and the solvent was evaporated in vacuo. The residue wasdiluted with ethyl acetate, and the organic layer was washed with asaturated aqueous solution of sodium hydrogen carbonate and dried overanhydrous magnesium sulfate. The residue obtained by evaporation of thesolvent was purified by silica gel column chromatography (eluent:hexane/ethyl acetate=2/1) to give 302 mg of tert-butyl(R)-N-(2-hydroxy-2-phenylethyl)-N-[2-[4-[(8-quinolinecarbonyl)amino]phenyl]ethyl]carbamate.

REFERENTIAL EXAMPLE 6

To a solution of 403 mg of tert-butyl(R)-N-(2-hydroxy-2-phenylethyl)-N-[2-[4-[(2-1H-imidazol-2-ylacetyl)amino]phenyl]ethyl]carbamatein 10 ml of acetonitrile were added 120 mg of potassium carbonate and164 mg of 2-fluorobenzyl bromide successively at room temperature. Thereaction solution was stirred at 50° C. for 12 hours. Insoluble matterswere filtered off using Celite, and the solvent was evaporated. Theresulting residue was purified by silica gel column chromatography togive 253 mg of tert-butyl(R)-N-[2-[4-[[2-[1-(2-fluorobenzyl)-1H-imidazol-2-yl]-acetyl]amino]phenyl]ethyl]-N-(2-hydroxy-2-phenylethyl)-carbamate.

REFERENTIAL EXAMPLE 7

To a solution of 13.4 g of(R)-2-[N-benzyl-N-[2-(4-nitrophenyl)ethyl]amino]-1-phenylethanol in 150ml of methanol were added 8.6 g of iron powder and 40 ml of a 2N aqueoushydrochloric acid solution. The reaction mixture was heated to refluxfor two hours, a 1N aqueous solution of sodium hydroxide was addedthereto, and the insoluble matters thus produced were filtered off usingCelite. The filtrate was concentrated in vacuo to remove the methanol.The resulting aqueous phase was extracted with chloroform, the organiclayer was dried over anhydrous magnesium sulfate, and the solvent wasevaporated in vacuo. The resulting residue was purified by silica gelcolumn chromatography (eluent: hexane/ethyl acetate=1/1) to give 11.45 gof (R)-2-[N-[2-(4-amino-phenyl)ethyl]-N-benzylamino]-1-phenylethanol.

REFERENTIAL EXAMPLE 8

To 502 mg of(R)-2-[N-[2-(4-aminophenyl)ethyl]-N-benzylamino]-1-phenylethanol wereadded 336 mg of ethyl 2-(3-methylpyridin-2-yl)acetate and 10 ml ofxylene. The reaction mixture was refluxed for nine hours, and thesolvent was evaporated in vacuo. The resulting residue was purified bysilica gel column chromatography (eluent: hexane/ethyl acetate=1/3) togive 222 mg of(R)-4′-[2-[N-benzyl-N-(2-hydroxy-2-phenylethyl)amino]ethyl3-2-(3-methylpyridin-2-yl)acetanilide.

REFERENTIAL EXAMPLE 9

To a solution of 0.96 g of 2-fluoroacetophenone in 20 ml oftetrahydrofuran was added 2.65 g of benzyltrimethylammonium tribromide.The reaction mixture was stirred at room temperature for 30 minutes,insoluble matters were filtered off, and the solvent was concentrated invacuo. The resulting residue was dissolved in 40 ml of 2-butanone, then1.81 g of N-benzyl-4-nitrophenethylamine and 0.92 g of diisopropylethylamine were added, and the reaction mixture was heated to reflux forone hour. The solvent was evaporated in vacuo, ethyl acetate was addedthereto, and the mixture was washed with water and a saturated salinesolution successively. The organic layer was dried over anhydrousmagnesium sulfate and evaporated in vacuo. The resulting residue wasdissolved in 40 ml of methanol, 0.34 g of sodium borohydride was addedthereto, and the reaction mixture was stirred at room temperature forone hour. The solvent was evaporated in vacuo, ethyl acetate was added,and the mixture was washed with water and a saturated saline solutionsuccessively. The organic layer was dried over anhydrous magnesiumsulfate and evaporated in vacuo. The resulting residue was purified bysilica gel column chromatography (eluent: chloroform) to give 1.95 g of2-[N-benzyl-N-[2-(4-nitrophenyl)ethyl]amino]-1-(2-fluorophenyl)ethanol.

REFERENTIAL EXAMPLE 10

A reaction mixture of 5.12 g of methyl 2-pyridylacetate, 5.14 g of4-aminobenzyl cyanide and 50 ml of xylene was heated to reflux for 24hours. An appropriate amount of the solvent was evaporated, diethylether was added to the residue, and the resulting crystals were taken byfiltration to give 5.65 g of 4′-cyanomethyl-2-(2-pyridyl)acetanilide.

REFERENTIAL EXAMPLE 11

To a solution of 640 mg of4′-cyanomethyl-2-(4,6-dimethyl-2-pyridyl)acetanilide in 15 ml oftetrahydrofuran was added 15 ml of an ethanolic suspension of a Raneynickel, and concentrated aqueous ammonia was added to adjust the pH ofthe mixture to about 10. The mixture was stirred at room temperature forone hour in a hydrogen atmosphere under atmospheric pressure. Thereaction mixture was filtered using Celite, and the solvent wasevaporated in vacuo to give 640 mg of4′-(2-aminomethyl)-2-(4,6-dimethyl-2-pyridyl)acetanilide.

REFERENTIAL EXAMPLE 12

To a solution of 630 mg of4′-(2-aminomethyl)-2-(4,6-dimethyl-2-pyridyl)acetanilide in 20 ml oftoluene was added 0.27 ml of benzaldehyde, and the mixture was heated toreflux for three hours using a Dean-Starke apparatus. The reactionmixture was filtered, and the solvent was evaporated in vacuo. Asolution of the resulting residue in 30 ml of methanol was cooled at 0°C., 63 mg of sodium borohydride was added, and the mixture was stirredat 0° C. for one hour. About one-half of the solvent of the reactionmixture was evaporated in vacuo, water and ethyl acetate were added tothe residue, the organic layer was washed with a saturated salinesolution twice and dried over anhydrous magnesium sulfate and thesolvent was evaporated in vacuo. To a solution of the resulting residuein 50 ml of isopropanol was added 0.26 ml of (R)-styrene oxide, and themixture was heated to reflux for 12 hours. The solvent was evaporated invacuo, and the resulting residue was purified by silica gel columnchromatography (eluent: chloroform/methanol=100/3) to give 920 mg of(R)-4′-[2-[N-benzyl-N-(2-hydroxy-2-phenylethyl)-amino]ethyl]-2-(4,6-dimethyl-2-pyridyl)acetanilide.

EXAMPLE 1

A 4N hydrogen chloride-ethyl acetate solution (10 ml) was added to 10 mlof an ethanolic solution of 458 mg of tert-butyl(R)-N-(2-hydroxy-2-phenylethyl)-N-[2-[4-[(2-pyridinecarbonyl)amino]phenyl]ethyl]carbamate.The reaction solution was stirred at room temperature for three hours,and the solvent was then evaporated in vacuo. The obtained crudecrystals were recrystallized from methanol-ethanol-ethyl acetate to give289 mg of(R)-4′-[2-[(2-hydroxy-2-phenyl-ethyl)amino]ethyl]-2-pyridinecarboxanilidedihydrochloride.

The compounds of Examples 2 to 33 were prepared by the same manner as inExample 1.

EXAMPLE 2(R)-4′-[2-[(2-Hydroxy-2-phenylethyl)amino]ethyl]-3-pyridinecarboxanilidedihydrochloride EXAMPLE 3(R)-41-[2-[(2-Hydroxy-2-phenylethyl)aminolethyl]-8-quinolinecarboxanilidedihydrochloride EXAMPLE 4(R)-4′-[2-[(2-Hydroxy-2-phenylethyl)amino]ethyl]-(E)-3-(2-pyridyl)acrylicanilide dihydrochloride EXAMPLE 5(R)-2-(Benzothiazol-2-yl)-4′-[2-[(2-hydroxy-2-phenyl-ethyl)amino]ethyl]acetanilidedihydrochloride EXAMPLE 6(R)-4′-[2-[(2-Hydroxy-2-phenylethyl)amino]ethyl]-2-(imidazo[2,1-b]thiazol-3-yl)acetanilidedihydrochloride EXAMPLE 7(R)-4′-[2-[(2-Hydroxy-2-phenylethyl)amino]ethyl]-2-(2-methylthiazol-4-yl)acetanilidehydrochloride EXAMPLE 8(R)-4′-[2-[(2-Hydroxy-2-phenylethyl)amino]ethyl]-2-(1H-imidazol-2-yl)acetanilidedihydrochloride EXAMPLE 9(R)-4′-[2-[(2-Hydroxy-2-phenylethyl)amino]ethyl]-2-(1H-tetrazol-5-yl)acetanilidehydrochloride EXAMPLE 10(R)-4′-[2-[(2-Hydroxy-2-phenylethyl)amino]ethyl]-2-(5-sulfanyl-1H-1,2,4-triazol-3-yl)acetanilidehydrochloride EXAMPLE 11(R)-2-(2-Aminothiazol-4-yl)-4′-[2-[(2-hydroxy-2-phenyl-ethyl)amino]ethyl]-2-oxoacetanilidedihydrochloride EXAMPLE 12(R)-2-(5-Amino-1,2,4-thiadiazol-3-yl)-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilidedihydrochloride EXAMPLE 13(R)-2-(5-Ethoxycarbonylamino-1,2,4-thiadiazol-3-yl)-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilidehydrochloride EXAMPLE 14 (R)-2-[(2-(3-Fluorophenylamino)thiazol-4-yl)-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilidedihydrochloride EXAMPLE 15(R)-2-(2-Chloropyridin-6-yl)-4′-[2-[(2-hydroxy-2-phenyl-ethyl)amino]ethyl]acetanilidehydrochloride EXAMPLE 16(R)-2-(2-Benzyloxypyridin-6-yl)-4′-(2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilidehydrochloride EXAMPLE 17(R)-4′-[2-[(2-Hydroxy-2-phenylethyl)amino]ethyl]-2-[l-(2-methyl-3-propenyl)-1H-imidazol-2-yl)acetanilidedihydrochloride EXAMPLE 18(R)-2-(1-Benzyl-1H-imidazol-4-yl)-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilidedihydrochloride EXAMPLE 19(R)-2-[1-(2-Chlorobenzyl)-1H-imidazol-4-yl]-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilidedihydrochloride EXAMPLE 20(R)-2-[1-(3-Chlorobenzyl)-1H-imidazol-4-yl)-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilidedihydrochloride EXAMPLE 21(R)-2-[1-(4-Chlorobenzyl)-1H-imidazol-4-yl]-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilidedihydro-chloride EXAMPLE 22(R)-2-[1-(4-Fluorobenzyl)-1H-imidazol-2-yl]-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilidedihydrochloride EXAMPLE 23(R)-2-[1-(4-Chlorobenzyl)-1H-imidazol-2-yl]-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilidedihydrochloride EXAMPLE 24(R)-2-[1-(4-Bromobenzyl)-1H-imidazol-2-yl]-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilidedihydrochloride EXAMPLE 25(R)-4′-[2-[(2-Hydroxy-2-phenylethyl)amino]ethyl]-2-[1-(4-iodobenzyl)-1H-imidazol-2-yl]acetanilidedihydrochloride EXAMPLE 26(R)-4′-[2-[(2-Hydroxy-2-phenylethyl)amino]ethyl]-2-[1-(4-trifluoromethylbenzyl)-1H-imidazol-2-yl]acetanilidedihydrochloride EXAMPLE 27(R)-4′-[2-[(2-Hydroxy-2-phenylethyl)amino]ethyl]-2-[1-(2-naphthyl)-1H-imidazol-2-yl]acetanilidedihydrochloride EXAMPLE 28(R)-2-[1-(4-Fluorobenzyl)-5-methyl-1H-imidazol-2-yl]-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilidedihydrochloride EXAMPLE 29(R)-2-[1-(4-Fluorobenzyl)-4-methyl-1H-imidazol-2-yl]-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilidedihydrochloride EXAMPLE 30(R)-2-[1-(4-Fluorobenzyl)-1H-tetrazol-5-yl]-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilidehydrochloride EXAMPLE 31(R)-2-[2-(3,4-Dichlorobenzyl)-1H-tetrazol-5-yl]-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilidehydrochloride EXAMPLE 32(R)-2-[2-(4-Fluorobenzyl)-1H-tetrazol-5-yl]-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilidehydrochloride EXAMPLE 33(R)-2-[1-(3,4-Dichlorobenzyl)-1H-tetrazol-5-yl]-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilidehydrochloride EXAMPLE 34

To a solution of 175 mg of tert-butyl(R)-N-[2-[4-[2-(1H-1,2,4-triazol-3-yl)acetylaminolphenyl]ethyl]N-(2-hydroxy-2-phenylethyl)carbamate in 5 ml of methanol was added 4 ml of a solution of 4Nhydrogen chloride in ethyl acetate. The mixture was stirred at roomtemperature for three hours, the solvent was filtered off, and theresulting powder was washed with ethanol. The resulting powder was driedto give 125 mg of(R)-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]-2-(1H-1,2,4-triazol-3-yl)acetanilidedihydrochloride.

The compounds of Examples 35 to 40 were prepared by the same manner asin Example 34.

EXAMPLE 35(R)-2-(5-Benzylsulfanyl-1H-1,2,4-triazol-3-yl)-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilidedihydrochloride EXAMPLE 36(R)-2-(2-Acetamidothiazol-4-yl)-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilidehydrochloride EXAMPLE 37(R)-4′-[2-[(2-Hydroxy-2-phenylethyl)amino]ethyl]-2-(2-methanesulfonamidothiazol-4-yl)acetanilidehydrochloride EXAMPLE 38(R)-2-(2-Guanidinothiazol-4-yl)-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilidedihydrochloride EXAMPLE 39(R)-4′-[2-[(2-Hydroxy-2-phenylethyl)aminolethyl]-2-(2-phenylaminothiazol-4-yl)acetanilidehydrochloride EXAMPLE 40(R)-4′-[2-[(2-Hydroxy-2-phenylethyl)amino]ethyl]-2-[1-(4-nitrobenzyl)-1H-imidazol-2-yl]acetanilidehydrochloride EXAMPLE 41

To 690 mg of tert-butyl(R)-N-[2-[4-[2-(2-amino-thiazol-4-yl)acetamino]phenyl]ethyl]-N-[(2-hydroxy-2-phenyl)ethyl]carbamatewere added 30 ml of methanol and 15 ml of a solution of 4N hydrogenchloride in ethyl acetate, and the mixture was stirred at roomtemperature for two hours. The solvent was evaporated in vacuo, and theresidue was purified by a reverses phase column chromatography (eluent:water/methanol 2/1) to give 310 mg of(R)-2-(2-aminothiazol-4-yl)-4′-[2-(2-hydroxy-2-phenylethyl)amino]-ethyl]acetanilidedihydrochloride.

The compounds of Examples 42 to 57 were prepared by the same manner asin Example 41.

EXAMPLE 42(R)-4′-[2-[(2-Hydroxy-2-phenylethyl)amino]ethyl]-(2-amino-thiazol-4-yl)carboxanilidehydrochloride EXAMPLE 43(R)-2-(2-Amino-5-methylthiazol-4-yl)-4′-2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilidedihydrochloride EXAMPLE 44(R)-2-(2-Aminothiazol-4-yl)-2-methyl-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]propionanilidehydrochloride EXAMPLE 45(R)-4′-[2-[(2-Hydroxy-2-phenylethyl)amino]ethyl]-(2-amino-4,5,6,7-tetrahydrobenzothiazol-4-yl)carboxanilidedihydrochloride EXAMPLE 46(R)-4′-[2-[(2-Hydroxy-2-phenylethyl)amino]ethyl]-2-(imidazo[2,1-b]thiazol-6-yl)acetanilidehydrochloride EXAMPLE 47(R)-2-(2-Benzyl-1H-1,2,4-triazol-3-yl)-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilidehydrochloride EXAMPLE 48(R)-2-(1-Benzyl-1H-1,2,4-triazol-3-yl)-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilidehydrochloride EXAMPLE 49(R)-2-(3-Benzyl-2-thioxothiazol-4-yl)-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilidehydrochloride EXAMPLE 50(R)-4′-[2-[(2-Hydroxy-2-phenylethyl)amino]ethyl]-(5,6,7,8-tetrahydroquinolin-8-yl)carboxanilidedihydrochloride EXAMPLE 51(R)-4′-[2-[(2-Hydroxy-2-phenylethyl)amino]ethyl]-2-(1-phenyl-1H-imidazol-2-yl)acetanilidedihydrochloride EXAMPLE 52(R)-4′-[2-[(2-Hydroxy-2-phenylethyl)amino]ethyl]-2-[(1-(4-isopropylbenzyl)-1H-imidazol-2-yl)acetanilidedihydrochloride EXAMPLE 53(R)-4′-[2-[(2-Hydroxy-2-phenylethyl)amino]ethyl]-2-[(1-(4-phenylbenzyl)-1H-imidazol-2-yl)acetanilidedihydrochloride EXAMPLE 54(R)-2-[1-(2-Chlorobenzyl)-1H-imidazol-2-yl]-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilidedihydrochloride EXAMPLE 55(R)-2-[1-(3-Chlorobenzyl)-1H-imidazol-2-yl]-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilidedihydrochloride EXAMPLE 56(R)-2-[1-(3,4-Dichlorobenzyl)-1H-imidazol-2-yl]-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilidedihydrochloride EXAMPLE 57(R)-4′-[2-[(2-Hydroxy-2-phenylethyl)amino]ethyl]-2-[(1-(2-pyridyl)methyl-1H-imidazol-2-yl)acetanilidedihydrochloride

The compound of Example 58 was prepared by the same manner as in Example1.

EXAMPLE 58(R)-2-(2-aminopyridin-6-yl)-4′-[2-[(2-hydroxy-2-phenyl-ethyl)amino]ethyl]acetanilidedihydrochloride EXAMPLE 59

To a solution of tert-butyl(R)-N-[2-[4-[[2-(2-amino-thiazol-4-yl)-2-oxoacetyl]amino]phenyl]ethyl]-N-(2-hydroxy-2-phenylethyl)carbamate in 30 ml of methanol was added 130 mg of sodium borohydride atroom temperature. The reaction mixture was stirred at room temperaturefor three hours, and the solvent was evaporated in vacuo. The residuewas dissolved in 5 ml of methanol, and to this reaction solution wasadded 10 ml of a solution of 4N hydrogen chloride-ethyl acetate. Thereaction solution was stirred at room temperature for eight hours andthe solvent was evaporated in vacuo. The residue was purified by silicagel column chromatography (eluent: chloroform/methanol=5/1). Theresulting residue was purified by reversed phase column chromatography(eluent: water/methanol=2/1) to give 77 mg of(R)-2-(2-amino-thiazol-4-yl)-2-hydroxy-4′-[2-(2-hydroxy-2-phenylethyl)-amino]acetanilidehydrochloride.

EXAMPLE 60

To 349 mg of tert-butyl(R)-N-[2-[4-[[2-(2-benzyl-oxypyridin-6-yl)acetyl]amino]phenyl]ethyl]-N-(2-hydroxy-2-phenylethyl)carbamate were added 478 mg of pentamethylbenzene and 5 ml oftrifluoroacetic acid successively. The reaction solution was stirred atroom temperature for four hours, and the solvent was evaporated invacuo. To the residue were added water and potassium carbonate to makethe solution basic, and the aqueous phase was extracted with a mixedsolvent of chloroform and tetrahydrofuran. The organic layer was driedover anhydrous magnesium sulfate, and the solvent was evaporated invacuo. The residue was purified by silica gel column chromatography(eluent: chloroform/methanol=10/1→5/1). To an ethanolic solution of theresulting residue was added 100 μl of a 4N hydrogen chloride-ethylacetate solution, and then the solvent was evaporated in vacuo. Theresulting crude crystals were recrystallized from ethanol-ethyl acetateto give 65 mg of(R)-2-(2-benzyloxypyridin-6-yl)-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilidehydrochloride.

The compounds of Examples 61 to 76, 83 and 85 were prepared by the samemanner as in Example 1; and the compounds of Examples 77 to 82 wereprepared by the same manner as in Example 41.

EXAMPLE 61(R)-4′-[2-[(2-Hydroxy-2-phenylethyl)aminolethyl]-2-(2-methylpropyl-1H-imidazol-2-yl)acetanilidedihydrochloride EXAMPLE 62(R)-2-[1-(2-Fluorobenzyl)-1H-imidazol-2-yl]-4′-[2-(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilidedihydrochloride EXAMPLE 63(R)-[1-(3-Fluorobenzyl)-1H-imidazol-2-yl]-4′-[2-(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilidedihydrochloride EXAMPLE 64(R)-2-[1-(2,4-Difluorobenzyl)-1H-imidazol-2-yl]-4′-[2-(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilidedihydrochloride EXAMPLE 65(R)-2-[1-(2,6-Difluorobenzyl)-1H-imidazol-2-yl]-4′-[2-(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilidedihydrochloride EXAMPLE 66(R)-2-[1-(3,5-Difluorobenzyl)-1H-imidazol-2-yl]-4-[2-(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide dihydrochlorideEXAMPLE 67(R)-2-[1-(2,5-Difluorobenzyl)-1H-imidazol-2-yl])-4′-[2-(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilidedihydrochloride EXAMPLE 68(R)-2-[1-(3,4-Difluorobenzyl)-1H-imidazol-2-yl3-4′-[2-(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilidedihydrochloride EXAMPLE 69(R)-4′-[2-[(2-Hydroxy-2-phenylethyl)amino]ethyl]-2-[1-(2,3,6-trifluorobenzyl)-1H-imidazol-2-yl]acetanilidedihydrochloride EXAMPLE 70(R)-4′-[2-[(2-Hydroxy-2-phenylethyl)amino]ethyl]-2-[l-(2,4,5-trifluorobenzyl)-1H-imidazol-2-yl]acetanilidedihydrochloride EXAMPLE 71(R)-4′-[2-[(2-Hydroxy-2-phenylethyl)amino]ethyl]-2-[1-(3,4,5-trifluorobenzyl)-1H-imidazol-2-yl]acetanilidedihydrochloride EXAMPLE 72(R)-4′-[2-[(2-Hydroxy-2-phenylethyl)amino]ethyl]-2-[1-(2,3,4,5,6-pentafluorobenzyl)-1H-imidazol-2-yl]acetanilidedihydrochloride EXAMPLE 73(R)-4′-[2-[(2-Hydroxy-2-phenylethyl)amino]ethyl]-2-[1-(3-iodobenzyl)-1H-imidazol-2-yl]acetanilidedihydrochloride EXAMPLE 74(R)-2-[1-(2,6-Dichiorobenzyl)-1H-imidazol-2-yl]-4′-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilidehydrochloride EXAMPLE 75(R)-2-[1-(4-Cyanobenzyl)-1H-imidazol-2-yl]-4′-[2-(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilidedihydrochloride EXAMPLE 76(R)-4′-[2-[(2-Hydroxy-2-phenylethyl)amino]ethyl]-2-[1-(quinolin-2-yl)-1H-imidazol-2-yl]acetanilidetrihydrochloride EXAMPLE 77(R)-2-[1-(2-Chloro-6-fluorobenzyl)-1H-imidazol-2-yl]-4′-[2-(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilideEXAMPLE 78(R)-2-[1-(2-Chloro-4-fluorobenzyl)-1H-imidazol-2-yl]-4′-[2-(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilideEXAMPLE 79(R)-2-[1-(2,5-Dichiorobenzyl)-1H-imidazol-2-yl]-4′-[2-(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilidedihydrochloride EXAMPLE 80(R)-4′-[2-[(2-Hydroxy-2-phenylethyl)amino]ethyl]-2-[1-(2,3,4-trifluorobenzyl)-1H-imidazol-2-yl]acetanilidedihydrochloride EXAMPLE 81(R)-4′-[2-[(2-Hydroxy-2-phenylethyl)amino]ethyl]-2-[1-(4-methoxycarbonylbenzyl)-1H-imidazol-2-yl]acetanilidedihydrochloride EXAMPLE 82(R)-4′-[2-[(2-Hydroxy-2-phenylethyl)amino]ethyl]-2-[1-[(piperidine-1-carbonyl)benzyl]-1H-imidazol-2-yl]acetanilidedihydrochloride EXAMPLE 83(R)-4′-[2-[(2-Hydroxy-2-phenylethyl)amino]ethyl]-2-(1-pyrazolyl)acetanilidehydrochloride EXAMPLE 84(R)-4′-[2-[(2-Hydroxy-2-phenylethyl)amino]ethyl]-2-(1,2,4-triazol-1-yl)acetanilidedihydrochloride EXAMPLE 85(R)-2-(2-Aminobenzimidazol-1-yl)-4′-[(2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilidedihydrochloride EXAMPLE 86

To a solution of 20.1 g of4′-[2-[N-benzyl-N-(2-hydroxy-2-phenylethyl)amino]ethyl]-2-(2-pyridyl)acetanilide in 400 ml of methanol was added 5.96 g of 10%palladium-carbon. The reaction solution was stirred for six hours in ahydrogen atmosphere under atmospheric pressure. Insoluble matters werefiltered off using Celite and the filtrate was concentrated in vacuo. Toa methanolic solution of the resulting residue was added 10.8 ml of a 4Nhydrogen chloride-ethyl acetate solution, and the solvent was evaporatedin vacuo. The resulting crude crystals were recrystallized frommethanol-ethanol to give(R)-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]-2-(2-pyridyl)acetanilidehydrochloride.

The compounds of 87 to 90 were prepared by the same manner as in Example86.

EXAMPLE 87(R)-4′-[2-[(2-Hydroxy-2-phenylethyl)amino]ethyl]-2-(3-pyridyl)acetanilidehydrochloride EXAMPLE 88(R)-4′-[2-[(2-Hydroxy-2-phenylethyl)amino]ethyl]-2-(4-pyridyl)acetanilidehydrochloride EXAMPLE 89(R)-4′-[2-[(2-Hydroxy-2-phenylethyl)amino]ethyl]-3-(2-pyridyl)propionanilidehydrochloride EXAMPLE 90(R)-4′-[2-[(2-Hydroxy-2-phenylethyl)amino]ethyl]-2-[(1-phenylethyl)-1H-imidazol-2-yl]acetanilidedihydrochloride EXAMPLE 91

(R)-2-(1H-Benzimidazol-2-yl)-4′-[4-[2-[N-benzyl-N-(2-hydroxy-2-phenylethyl)amino]ethyl]phenyl]acetanilide(240 mg) was dissolved in 30 ml of ethanol, then 170 mg of 10%palladium-carbon was added thereto and the mixture was stirred for ninehours in a hydrogen atmosphere under atmospheric pressure. The catalystwas filtered off, the solvent was evaporated in vacuo, and the residuewas washed with ethanol-ethyl acetate to give 200 mg of(R)-2-(1H-benzimidazol-2-yl)-4′-[2-[(2-hydroxy-2-phenylethyl)amino]-ethyl]acetanilide.

The compounds of Examples 92 and 93 were prepared by the same manner asin Example 86.

EXAMPLE 92(R)-4′-[2-[(2-Hydroxy-2-phenylethyl)amino]ethyl]-2-(3-methylpyridin-2-yl]acetanilidehydrochloride EXAMPLE 93(R)-4′-[2-[(2-Hydroxy-2-phenylethyl)amino]ethyl]-2-(2-pyrazinyl)acetanilidehydrochloride EXAMPLE 94

(R)-4′-[4-[2-[N-Benzyl-N-(2-hydroxy-2-phenylethyl)-amino]ethyl]phenyl]-2-(1-benzyl-1H-imidazol-2-yl)acetanilide(350 mg) was dissolved in 20 ml of ethanol, then 130 mg of 10%palladium-carbon was added thereto, and the mixture was stirred for 17.5hours in a hydrogen atmosphere under atmospheric pressure. The catalystwas filtered off, the solvent was evaporated in vacuo, and the residuewas purified by silica gel column chromatography (eluent:chloroform/methanol/concentrated aqueous ammonia=200/10/1). Theresulting oily substance was dissolved in methanol, and 280 μl of a 4Nhydrogen chloride-ethyl acetate solution was added thereto. The mixturewas filtered after adding active carbon was added thereto, and thesolvent was evaporated in vacuo to give 200 mg of(R)-2-(1-benzyl-1H-imidazol-2-yl)-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilidedihydrochloride.

The compounds of Examples 95 and 97 were prepared by the same manner asin Example 91; the compounds of Examples 98 and 100 were prepared by thesame manner as in Example 94; and the compounds of Examples 99 and 101to 103 were prepared by the same manner as in Example 86.

EXAMPLE 95(R)-4′-[2-[(2-Hydroxy-2-phenylethyl)amino]ethyl]-2-(4-methyl-2-pyridyl)acetanilideEXAMPLE 96(R)-4′-[2-[(2-Hydroxy-2-phenylethyl)amino]ethyl]-2-(5-methyl-2-pyridyl)acetanilideEXAMPLE 97(R)-4′-[2-[(2-Hydroxy-2-phenylethyl)amino]ethyl]-2-(6-methyl-2-pyridyl)acetanilideEXAMPLE 984′-[(R)-2-[((R)-2-Hydroxy-2-phenylethyl)amino]propyl]-2-(2-pyridyl)acetanilidehydrochloride EXAMPLE 994′-[(S)-2-[((R)-2-Hydroxy-2-phenylethyl)aminolpropyl]-2-(2-pyridyl)acetanilidehydrochloride EXAMPLE 1002-(1-Benzyl-1H-imidazol-2-yl)-4′-[(S)-2-[((R)-2-hydroxy-2-phenylethyl)amino]propyl]acetanilidehydrochloride EXAMPLE 1014′-[2-[[2-Hydroxy-2-(2-fluorophenyl)ethyl]amino]ethyl]-2-(2-pyridyl)acetanilidehydrochloride EXAMPLE 1024′-[2-[[2-Hydroxy-2-(3-fluorophenyl)ethyl]amino]ethyl]-2-(2-pyridyl)acetanilidehydrochloride EXAMPLE 1034′-[2-[[2-Hydroxy-2-(4-fluorophenyl)ethyl]amino]ethyl]-2-(2-pyridyl)acetanilidehydrochloride EXAMPLE 104

To a solution of 805 mg of 4′-cyanomethyl-2-(2-pyrimidinyl)acetanilidein 30 ml of tetrahydrofuran were added 30 ml of an ethanolic solution ofa Raney nickel and 3 ml of concentrated aqueous ammonia. The reactionsolution was stirred for four hours in a hydrogen atmosphere underatmospheric pressure, then insoluble matters were filtered off usingCelite, and the solvent was evaporated. To the resulting residue wereadded 10 ml of 2-propanol, 300 mg of (R)-styrene oxide and 2 ml ofmethanol successively. The reaction mixture was heated to reflux for tenhours, and the solvent was evaporated. The residue was purified bysilica gel column chromatography (eluent: chloroform/methanol=10/1). Toa methanolic solution of the resulting residue was added 150 μl of 4Nhydrogen chloride-ethyl acetate solution, and the solvent was evaporatedin vacuo. The resulting residue was crystallized frommethanol-ethanol-ethyl acetate and then recrystallized fromethanol-diethyl ether to give 160 mg of(R)-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]-2-(2-pyrimidinyl]acetanilidehydrochloride.

The compounds of Examples 105 to 108 were prepared by the same manner asin Example 104; and the compound of Example 109 was prepared by the samemanner as in Example 91.

EXAMPLE 105(R)-4′-[2-[(2-Hydroxy-2-phenylethyl)amino]ethyl]-2-(2-quinolyl)acetanilidehydrochloride EXAMPLE 106(R)-4′-[2-[[2-Hydroxy-2-(3-chlorophenyl)ethyl]amino]-ethyl]-2-(2-pyridyl)acetanilidehydrochloride EXAMPLE 1074′-[2-[[2-Hydroxy-2-(3-pyridyl)ethyl]amino]ethyl]-2-(2-pyridyl)acetanilidehydrochloride EXAMPLE 108(R)-2-[1-(4-Chlorobenzyl)-1H-benzimidazol-2-yl]-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilidedihydrochloride EXAMPLE 109(R)-2-(4,6-Dimethyl-2-pyridyl)-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilideEXAMPLE 110

To 4′-(3-aminopropyl)-2-(2-pyridyl)acetanilide were added 10 ml of2-propanol and 600 mg of (R)-styrene oxide successively. The reactionmixture was heated to reflux for four hours, and the solvent wasevaporated. The residue was purified by silica gel column chromatography(eluent: chloroform/methanol=30/1Δ10/1). To a methanolic solution of theresulting residue was added 100 μl of a 4N hydrogen chloride-ethylacetate solution, and the solvent was evaporated in vacuo. The resultingcrude crystals were recrystallized from ethanol-diethyl ether to give 71mg of(R)-4′-[3-[(2-hydroxy-2-phenylethyl)aminolpropyl]-2-(2-pyridyl)acetanilidehydrochloride.

EXAMPLE 111

To a solution of 3.62 g of tert-butylN-[2-[4-[[2-(2-pyridyl)acetyl]amino]phenoxy]ethyl]carbamate in 30 ml ofmethanol was added 50 ml of a 4N hydrochloride-ethyl acetate solution.After the reaction solution was stirred at room temperature for eighthours, the solvent was evaporated in vacuo. To the residue were added anaqueous solution of sodium hydrogen carbonate and potassium carbonate toadjust to pH about 12. The resulting aqueous phase was extracted with amixed solvent of chloroform and tetrahydrofuran. The organic layer wasdried over anhydrous magnesium sulfate and concentrated, the resultingresidue was dissolved in 40 ml of methanol, and 1.02 g of (R)-styreneoxide was added thereto. After the reaction solution was heated toreflux for 26 hours, the solvent was evaporated in vacuo. The resultingresidue was purified by silica gel column chromatography (eluent:chloroform/methanol=30/1→10/1) and dissolved in methanol, 0.59 ml of a4N hydrogen chloride-ethyl acetate solution was added, and the solventwas evaporated in vacuo. The resulting crude crystals wererecrystallized from methanol-ethanol to give 320 mg of(R)-4′-[2-[(2-hydroxy-2-phenylethyl)-amino]ethoxy]-2-(2-pyridyl)acetanilidehydrochloride

EXAMPLE 112

To a solution of 490 mg of tert-butylN-[1,1-di-methyl-2-[4-[[2-(2-pyridyl)acetyl]amino]phenyl]ethyl]-carbamatein 10 ml of methanol was added 30 ml of a 4N hydrochloride-ethyl acetatesolution. After the reaction solution was stirred at room temperaturefor eight hours, the solvent was evaporated in vacuo. To the residuewere added an aqueous solution of sodium hydrogen carbonate andpotassium carbonate to adjust to pH about 12. The resulting aqueousphase was extracted with a mixed solvent of chloroform andtetrahydrofuran. The organic layer was dried over anhydrous magnesiumsulfate and concentrated, the resulting residue was dissolved in 2 ml of2-propanol and 2 ml of methanol, and 120 mg of (R)-styrene oxide wasadded thereto. After the reaction solution was heated to reflux for 24hours, the solvent was evaporated in vacuo. The resulting residue waspurified by silica gel column chromatography (eluent:chloroform/methanol=30/1→15/1) and dissolved in methanol, 0.1 ml of a 4Nhydrogen chloride-ethyl acetate solution was added, and the solvent wasevaporated in vacuo. The resulting residue was purified by silica gelcolumn chromatography (eluent: chloroform/methanol=5/1) and a reversedphase column chromatography (eluent: water/methanol=2/1→1/1) to give 35mg of(R)-4′-[2,2-dimethyl-2-[(2-hydroxy-2-phenylethyl)amino]ethyl]-2-(2-pyridyl)acetanilidehydrochloride.

The compound of Example 113 was prepared by the same manner as inExample 1.

EXAMPLE 113(R)-1-(4-[2-[(2-Hydroxy-2-phenylethyl)amino]ethyl]phenyl]-3-(2-pyridyl)ureadihydrochloride

As hereunder, physical and chemical properties of the compounds of theReferential Examples are given in Tables 1 and those of the compounds ofthe Examples are given in Tables 2.

The symbols in the tables have the following meanings.

Rex.: Referential Example No.

Ex.: Example No.

DATA: Physico-chemical properties

NMR: Nucleomagnetic resonance spectrum (TMS internal standard; DMSO-dwas used as a solvent unless otherwise specified)

mp: melting point

dec: decomposition

MS (m/z): mass spectrographic data (m/z)

Structure: structural formula

TABLE 1 Rex. DATA 1 NMR (CDCl₃) δ: 2.75(1H, dd, J=12.4, 8.8Hz),2.85-3.04 (5H, m), 4.70(1H, dd, J=8.8, 3.7Hz), 7.24-7.40(7H, m),8.10-8.20 (2H, m) 2 NMR (CDCl₃) δ: 1.44(9H, s), 2.75-3.10(2H, m),3.20-3.70 (4H, m), 4.93(1H, br), 7.25-7.40(7H, m), 8.14(2H, d, J=8.4Hz)3 NMR (CDCl₃) δ: 1.47(9H, s), 2.55-2.80(2H, m), 3.20-3.40 (2H, m),3.45-3.65(2H, m), 4.87(1H, m), 6.57-6.65(2H, m), 6.83-7.04(2H, m),7.25-7.40(5H, m) 4 NMR (CDCl₃) δ: 1.47(9H, s), 2.62-2.93(2H, m),3.14-3.58 (4H, m), 4.35(1H, brs), 4.90(1H, br), 7.06-7.40(7H, m),7.45-7.50 (1H, m), 7.67-7.72(2H, m), 7.90(1H, dt, J=2.0, 8.0Hz),8.25-8.31 (1H, m), 8.58-8.63(1H, m), 9.98(1H, brs) 5 NMR (CDCl₃) δ:1.49(9H, s), 2.64-2.90(2H, m), 3.16-3.60 (4H, m), 4.38(1H, brs),4.91(1H, br), 7.10-7.42(7H, m), 7.55(1H, dd, J=8.0, 4.4Hz), 7.74(1H, t,J=8.0Hz), 7.77-7.84(2H, m), 8.01(1H, d, J=8.0, 1.2Hz), 8.34(1H, d,J=8.4, 1.6Hz), 8.96(1H, d, J=7.6, 1.6Hz), 9.02(1H, d, J=4.4, 2.0Hz),13.61(1H, brs) 6 NMR (CDCl₃) δ: 1.47(9H, s), 2.60-2.80(2H, m), 3.15-3.55(4H, m), 3.78(2H, s), 4.36(1H, brs), 4.82-4.94(1H, m), 5.18 (2H, s),6.92-6.99(2H, m), 7.00-7.13(5H, m), 7.25-7.38 (6H, m), 7.42-7.48(2H, m),10.34(1H, brs) 7 NMR (CDCl₃) δ: 2.56-2.94(6H, m), 3.40-3.65(2H, m),3.80(1H, brs), 3.95(1H, d, 13.6Hz), 4.62(1H, dd, J=10.0, 3.2Hz),6.57-6.66(2H, m), 6.87-6.98(2H, m), 7.20-7.37(10H, m) 8 NMR (CDCl₃) δ:2.40(3H, s), 2.54-3.00(6H, m), 3.57(1H, d, J=13.6Hz), 3.88(2H, s),3.95(1H, d, J=13.6Hz), 4.62(1H, dd, J=10.4, 3.6Hz), 7.00-7.75(16H, m),8.44(1H, d, J=4.4Hz), 9.66(1H, brs) 9 NMR (CDCl₃) δ: 2.58-2.65(1H, m),2.75-3.00(5H, m), 3.59(1H, d, J=13.2Hz), 3.95(1H, d, J=13.2Hz), 5.01(1H,dd, J=10.0, 3.2Hz), 6.97-7.03(1H, m), 7.12-7.35(9H, m), 7.48-7.56(1H,m), 8.04-8.13(2H, m) 10  NMR (CDCl₃) δ: 3.70(2H, s), 3.88(2H, s),7.23-7.32 (4H, m), 7.54-7.62(2H, m), 7.71(1H, dt, J=7.6, 1.6Hz),8.63(1H, d), 10.04(1H, brs) 11  NMR (CDCl₃) δ: 2.26(3H, s), 2.39(3H, s),2.57(2H, t, J=7.2Hz), 2.72(2H, t, J=7.2Hz), 3.72(2H, s), 6.95(1H, s),7.01(1H, s), 7.11(2H, d, J=8.8Hz), 7.51(2H, d, J=8.8Hz), 10.17(1H, s)12  NMR δ: 2.32(3H, s), 2.41(3H, s), 2.90-3.19(6H, m), 3.75(2H, s),4.01(2H, s), 4.89(1H, dt, J=7.6, 3.2Hz), 6.99-7.71(16H, m), 10.26(1H, s)

TABLE 2 Ex. DATA  1 mp: 223-225° C., NMR δ: 2.95-3.28(6H, m),4.98-5.07(1H, m), 7.23-7.44(6H, m), 7.65-7.75(1H, m), 7.88(2H, d, J=8.4Hz), 8.05-8.22(2H, m), 8.75(1H, d, J=4.4Hz), 8.97(1H, brs), 9.43(1H,brs), 10.65(1H, brs)  2 mp: 263-265° C., NMR δ: 2.92-3.10(3H, m),3.13-3.27(3H, m), 5.00(1H, dd, J=10.8, 2.8Hz), 7.24-7.44(8H, m),7.74-7.81(3H, m), 8.57(1H, d, J=8.0Hz), 8.81-8.96(2H, m), 9.20-9.30(2H,m), 10.71(1H, brs)  3 mp: 145-147° C., NMR δ: 2.94-3.10(3H, m),3.14-3.30(3H, m), 4.97-5.05(1H, m), 7.27-7.46(7H, m), 7.77-7.90(4 H, m),8.30(1H, dd, J=8.4, 1.6Hz), 8.60-8.71(2H, m), 8.89(1H, brs),9.10-9.30(2H, m), 13.12(1H, brs)  4 mp: 246-248° C. (dec), NMR δ:2.92-3.09(3H, m), 3.11-3.26(3H, m), 5.01(1H, dd, J=10.4, 2.8Hz),7.24(2H, d, J= 8.4Hz), 7.29-7.47(6H, m), 7.56-7.75(4H, m), 7.85(1H, d,J=8.0Hz), 8.11(1H, t, J=7.6Hz), 8.73(1H, d, J=4.4Hz), 8.92 (1H, brs),9.32(1H, brs), 10.69(1H, brs)  5 mp: 228-233° C. (dec), NMR δ:2.88-3.09(3H, m), 3.10-3.24(3H, m), 4.30(2H, s), 4.93-5.01(1H, m),6.19(1H, d, J= 3.6Hz), 7.18-7.27(2H, m), 7.28-7.53(7H, m), 7.57-7.62(2H,m), 7.97(1H, d, J=7.6Hz), 8.08(1H, d, J=8.0Hz), 8.83(1H, brs), 9.11(1H,brs), 10.57(1H, brs)  6 mp: 161-162° C., NMR δ: 2.86-3.24(6H, m),4.2492H, s), 4.97(1H, dd, J=9.6, 2.8Hz), 7.16-7.23(2H, m), 7.27-7.44(5H, m), 7.55(1H, s), 7.61(2H, d, J=8.4Hz), 7.85(1H, s), 8.27(1H, d,J=2.4Hz), 8.97(1H, brs), 9.47(1H, brs), 10.94(1H, brs)  7 NMR δ:2.70(3H, s), 2.86-3.27(6H, m), 3.85(2H, s), 5.00-5.05(1H, m),7.18-7.60(10H, m), 10.43(1H, s)  8 mp: 203-207° C., NMR δ: 2.92-3.08(3H,m), 3.10-3.22(3H, m), 4.28(2H, s), 5.01(1H, d, J=7.8Hz), 6.21(1H, brs),7.22(2H, d, J=8.3Hz), 7.25-7.63(4H, m), 8.93(1H, brs), 9.38(1H, brs),10.86(1H, s)  9 mp: 259-261° C., NMR δ: 2.90-3.10(3H, m), 3.10-3.25(3H,m), 4.15(2H, s), 4.97(1H, d, J=10.8Hz), 6.20(1H, d, J= 3.9Hz), 7.21(sH,3, J=8.8Hz), 7.30-7.42(5H, m), 7.57(2H, d, J=8.8Hz), 8.85(1H, brs),9.14(1H, brs), 10.58(1H, s) 10 mp: 210-213° C., NMR δ: 2.86-3.08(3H, m),3.12-3.22(3H, m), 3.73(2H, s), 4.91-4.98(1H, m), 6.19(1H, d, J=3.9Hz),7.21(2H, d, J=8.3Hz), 7.29-7.42(5H, m), 7.54(2H,d, J=8.3Hz), 8.78(1H,brs), 8.99(1H, brs), 10.35(1H, s), 13.21(1H, brs), 13.34(1H, brs) 11 mp:205-210° C. (dec), NMR δ: 2.90-3.25(6H, m), 4.95-5.04(1H, m),7.23-7.44(7H, m), 7.67-7.75(2H, m), 8.15(1 H, s), 8.88(1H, brs),9.25(1H, brs) 12 mp: 244-246° C., NMR δ: 2.90-3.08(3H, m), 3.10-3.20(3H,m), 3.67(2H, s), 5.00(1H, dd, J=24, 10.02Hz), 7.192H, d, J=8.3Hz),7.28-7.42(5H, m), 7.57(2H, d, J=8.3Hz), 8.90(1H, s), 9.31(1H, s),10.31(1H, s) 13 mp: 205-208° C., NMR δ: 1.27(3H, t, J=7.1Hz),2.88-3.08(3H, m), 3.12-3.22(3H, m), 3.86(2H, s), 4.27(2H, q, J=7.1 Hz),4.96(1H, d, J=8.3Hz), 6.20(1H, s), 7.19(2H, d, J=8.3Hz), 7.30-7.42(5H,m), 7.57(2H, d, J=8.3Hz), 8.81(1H, s), 9.10(1H, s), 10.33(1H, s),12.53(1H, s) 14 mp: 169-173° C., NMR δ: 2.88-3.22(6H, m), 3.66(2H, s),4.98(1H, dd, J=2.9, 13.1Hz), 6.72(1H, s), 7.19(2H, d, J= 8.3Hz),7.23-7.42(8H, m), 7.59(2H, d, J=8.3Hz), 7.72-7.78(1H, m), 8.85(1H, s),9.18(1H, brs), 10.24(1H, brs), 10.55 (1H, s) 15 mp: 248-251° C., NMR δ:2.90-3.08(3H, m), 3.09-3.21(3H, m), 3.88(2H, s), 5.02(1H, dd, J=10.0,2.4Hz), 6.20(1H, brs), 7.16-7.22(2H, m), 7.28-7.46(7H, m), 7.57-7.63(2H,m), 7.84(1H, t, J=7.2Hz), 8.95(1H, brs), 9.40(1H, brs), 10.48 (1H, brs)16 mp: 237-238° C., NMR δ: 2.87-3.24(6H, m), 3.77(2H, s), 4.93-5.03(1H,m), 5.32(2H, s), 6.20(1H, d, J=4.0Hz), 6.73 (1H, d, J=8.0Hz), 6.99(1H,d, J=7.2Hz), 7.16-7.22(2H, m), 7.25-7.46(10H, m), 7.57-7.63(2H, s),7.67(1H, dd, J=8.4, 7.2Hz), 8.87(1H, brs), 9.24(1H, brs), 10.30(1H, brs)17 mp: 190-193° C., NMR δ: 1.68(3H, m), 2.90-3.10(3H, m), 3.10-3.20(3H,m), 4.32(2H, s), 4.67(1H, s), 4.83(2H, s), 4.94(1H, s), 4.99(1H, d,J=8.3Hz), 6.21(1H, brs), 7.21(2H, d, J=8.7Hz), 7.24-7.42(5H, m),7.56(2H, d, J=8.8Hz), 7.66 (2H, d, J=1.9Hz), 7.71(1H, d, J=1.9Hz),8.89(1H, brs), 9.30(1H, brs), 10.92(1H, s) 18 mp: 139-141° C., NMR δ:3.01(3H, brs), 3.15(3H, brs), 3.92(2H, s), 5.05(1H, d, J=10.3Hz),5.44(2H, s), 6.19(1H, brs), 7.19(2H, d, J=8.3Hz), 7.31-7.47(10H, m),7.60(2H, d, J=8.3Hz), 7.66(1H, s), 9.05(1H, brs), 9.35(1H, s), 9.60(1H,brs), 10.76(1H, s) 19 mp: 140-143° C., NMR δ: 2.99-3.09(3H, m), 3.16(3H,brs), 3.95(2H, s), 5.06(1H, d, J=10.4Hz), 5.57(2H, s), 6.19(1H, brs),7.19(2H, d, J=8.6Hz), 7.29-7.35(1H, m), 7.37-7.48(8H, m), 7.55-7.57(1H,m), 7.61(2H, d, J=8.6Hz), 9.09(1H, brs), 9.31(1H, d, J=1.5Hz), 9.65(1H,brs), 10.79(1H, s) 20 mp: 140-143° C., NMR δ: 3.01-3.09(3H, m), 3.16(3H,brs), 3.93(2H, s), 5.06(1H, d, J=10.3Hz), 5.47(2H, s), 6.15 (1H, brs),7.19(2H, d, J=8.6Hz), 7.29-7.33(1H, m), 7.38-7.46(7H, m), 7.61(2H, d,J=8.6Hz), 7.63(1H, s), 7.70(1H, s), 9.08 (1H, brs), 9.38(1H, s),9.63(1H, brs), 10.78(1H, s) 21 mp: 141-146° C., NMR δ: 2.96-3.14 (3H,m), 3.15(3H, brs), 3.91(2H, s), 5.04(1H, d, J=10.3Hz), 5.45(2H, s), 6.22(1H, brs), 7.19(2H, d, J=8.6Hz), 7.29-7.42(6H, m), 7.50(3H, s), 7.59(2H,d, J=8.6Hz), 7.65(1H, s), .02(1H, brs), 9.32 (1H, d, J=1.5Hz), 9.55(1H,brs), 10.73(1H, s) 22 mp: 230-235° C., NMR δ: 2.59-3.10(3H, m),3.10-3.25(3H, m), 4.47(2H, s), 5.01(1H, dd, J=10.3, 2.4Hz), 5.45(2H, s),6.21(1H, brs), 7.16-7.22(4H, m), 7.28-7.50(7H, m), 7.54(2H, d, J=8.3Hz),7.68(2H, dd, J=5.8, 1.9Hz), 8.94(1H, brs), 9.42(1H, brs), 10.98(1H, s)23 mP: 203-209° C., NMR δ: 2.90-3.10(3H, m), 3.10-3.20(3H, m),4.41-4.48(2H, m), 4.95-5.05(1H, m), 5.46(2H, s), 6.21(1H, brs), 7.20(2H,d, J=8.6Hz), 7.30-7.42(6H, m), 7.50-7.54(2H, m), 7.70(2H, s), 8.92(1H,brs), 9.39(1H, brs), 10.88-10.95(1H, m) 24 mp: 221-223° C., NMR δ:2.90-3.08(3H, m), 3.10-3.22(3H,m), 4.04(2H, s), 4.97(1H, d, J=9.1Hz),5.44(2H, s), 6.20 (1H, brs), 7.20(2H, d, J=8.1Hz), 7.30-7.41(9H, m),7.49(2H, d, J=8.6Hz), 7.55(2H, d, J=8.6Hz), 8.83(1H, brs), 9.16 (1H,brs), 10.76(1H, s) 25 mp: 222-225° C., NMR δ: 2.60-3.05(3H, m),3.10-3.20(3H, m), 4.43(2H, s), 5.01(1H, d, J=7.6Hz), 5.44(2H, s), 6.21(1H, brs), 7.15-7.23(4H, m), 7.26-7.46(5H, m), 7.51(2H, d, J=8.8Hz),7.65-7.72(4H, m), 8.94(1H, brs), 9.41(1H, brs), 10.93(1H, s), 14.72(1H,brs) 26 mp: 197-203° C., NMR δ: 2.80-3.10(3H, m), 3.10-3.25(3H, m),4.44(2H, s), 4.99(1H, d, J=8.0Hz), 5.61(2H, s), 6.21 (1H, brs), 7.17(2H,d, J=8.6Hz), 7.30-7.42(5H, m), 7.48(2H, d, J=8.5Hz), 7.54(2H, d,J=8.0Hz), 7.70(2H, d, J=8.1Hz), 7.72-7.77(2H, m), 8.90(1H, brs),9.34(1H, brs), 10.90(1H, s) 27 mp: 208-214° C., NMR δ: 2.90-3.10(3H, m),3.10-3.22(3H, m), 4.44(2H, s), 4.97(1H, d, J=9.7Hz), 5.62(2H, s), 6.20(1H, brs), 7.16(2H, d, J=8.0Hz), 7.30-7.55(10H, m), 7.70-7.94(6H, m),8.82(1H, brs), 9.14(1H, brs), 10.76(1H, s) 28 mp: 219-223° C., NMR δ:2.11(3H, s), 2.92-3.08(3H, m), 3.10-3.20(3H, m), 4.43(2H, s), 5.02(1H,dd, J=10.2, 2.4 Hz), 5.51(2H, s), 6.22(1H, brs), 7.14-7.34(7H, m),7.36-7.42(4H, m), 7.48-7.53(3H, m), 8.95(1H, brs), 9.43(1H, brs), 10.94(1H, s), 14.61(1H, brs) 29 mp: 204-207° C., NMR δ: 2.24(3H, s),2.80-3.10(3H, m), 3.10-3.50(3H, m), 4.43(2H, s), 5.01(1H, dd, J=10.3,2.5Hz), 5.39(2H, s), 6.21(1H, brs), 7.17-7.24(2H, m), 7.47(2H, dd,J=8.8, 5.4Hz), 7.552H, d, J=8.3Hz), 8.94(1H, brs), 9.40(1H, brs),11.00(1H, s), 14.70(1H, brs) 30 mp: 225-228° C., NMR δ: 2.90-3.07(3H,m), 3.10-3.23(3H, m), 4.28(2H, s), 4.97(1H, d, J=10.3Hz), 5.68(2H, s),6.20(1H, d, J=3.4Hz), 7.16-7.23(4H, m), 7.30-7.46(7H, m), 7.53(2H, d,J=8.8Hz), 8.82(1H, brs), 9.11(1H, brs), 10.63(1H, s) 31 mp: 232-235° C.,NMR δ: 2.90-3.10(3H,m), 3.10-3.25(3H, m), 4.03(2H, s), 4.98(1H, d,J=10.3Hz), 5.97(2H, s), 6.20(1H, brs), 7.19(2H, d, J=8.3Hz),7.29-7.42(6H, m), 7.55(2H, d, J=8.3Hz), 7.67-7.77(2H, m), 8.87(1H, brs),9.22(1H, brs), 10.49(1H, s), 14.61(1H, brs) 32 mp: 233-235° C., NMR δ:2.09-3.10(3H, m), 3.10-3.25(3H, m), 4.01(2H, s), 4.98(1H, d, J=10.3Hz),5.91(2H, s), 6.19(1H, brs), 7.17-7.48(11H, m), 7.55(2H, d, J=8.3Hz),8.85(1H, brs), 9.18(1H, brs), 10.47(1H, s) 33 mp: 240-242° C., NMR δ:2.90-3.10(3H, m), 3.10-3.25(3H, m), 4.32(2H, s), 4.98(1H, dt, J=10.3,3.4Hz), 5.72(2H, s), 6.20(1H, d, J=3.9Hz), 7.20(2H, d, J=8.3Hz),7.30-7.40(6H, m), 7.51(2H, d, J=8.8Hz), 7.62(1H, d, J=8.3Hz), 7.67 (1H,d, J=2.0Hz), 8.86(1H, brs), 9.17(1H, brs), 10.67(1H, s) 34 mp: 221-224°C., NMR δ: 2.90-3.07(3H, m), 3.10-3.20(3H, m), 4.05(2H, s), 5.00(2H, dd,J=2.7, 10.2Hz), 7.21(2H, d, J=8.6Hz), 7.29-7.42(5H,m), 7.58(2H, d,J=8.6Hz), 8.83(1H, s), 8.91(1H, brs), 9.32(1H, brs), 10.62(1H, s) 35 mp:222-224° C., NMR δ: 2.89-3.07(3H, m), 3.12-3.21(3H, m), 3.84(2H, s),4.33(2H, s), 4.98(1H, dd, J=2.4, 10.2 Hz), 7.20(2H, d, J=8.3Hz),7.22-7.42(10H, m), 7.58(2H, d, J=8.3Hz), 8.87(1H, brs), 9.22(1H, brs),10.44(1H, s) 36 mp: 242-245° C., NMR δ: 2.11(3H, s), 2.99-3.06(3H, m),3.09-3.21(3H, m), 3.68(2H, s), 5.00(1H, dd, J=2.1, 10.2Hz), 6.02(1H,brs), 6.98(1H, s), 7.18(2H, d, J=8.1Hz), 7.28-7.42(5H, m), 7.58(2H, d,J=8.1Hz), 8.89(1H, brs), 9.30(1H, brs), 10.25(1H, s), 12.10(1H, s) 37mp: 252-256° C., NMR δ: 2.89(3H, s), 2.91-3.07(3H, m), 3.11-3.21(3H, m),3.65(2H, s), 4.95-5.02(1H, m), 6.20 (1H, brs), 6.58(1H, s), 7.20(2H, d,J=8.6Hz), 7.28-7.42(5H, m), 7.57(2H, d, J=8.6Hz), 8.87(1H, brs),9.24(1H, brs), 10.39 (1H, s), 12.56(1H, s) 38 mp: >230° C. (dec.), NMRδ: 2.88-3.22(6H,m), 3.73(2H, s), 3.65(2H, s), 5.00(1H, dd, J=2.0,10.0Hz), 6.20(1H, brs), 7.12(1H, s), 7.18(2H, d, J=8.8Hz), 7.28-7.42(5H,m), 7.59(2H, d, J=8.8Hz), 8.39(4H, brs), 8.91(1H, brs), 9.32(1H, brs),10.41(1H, s), 12.60(1H, s) 39 mp: 177-181° c., NMR δ: 2.90-3.10(3H, m),3.10-3.25(3H, m), 3.67(2H, s), 5.00(1H, dd, J1=10.0, 2.0Hz), 6.68 (1H,s), 6.97(1H, t, J=7.2Hz), 7.19(2H, d, J=8.4Hz), 7.27-7.42(9H, m),7.59(2H, d, J=8.0Hz), 8.90(1H, brs), 9.29(1H, brs), 10.29(1H, s),10.54(1H, brs) 40 mp: 237-243° C., NMR δ: 2.90-3.06(3H, m),3.06-3.20(3H, m), 4.45(2H, s), 5.01(1H, dd, J=7.8, 2.0Hz), 5.70(2H, s),6.21(1H, brs), 7.14(2H, d, J=8.8Hz), 7.29-7.42(5H, m), 7.46(2H, d,J=8.8Hz), 7.54(2H, d, J=8.8Hz), 7.77(2H, dd, J=14.4, 2.0Hz), 8.13(2H, d,J=8.4Hz), 8.94(1H, brs), 9.41(1H, brs), 10.95(1H, s) 41 mp: 151-159° C.,NMR δ: 2.90-3.10(3H, m), 3.10-3.20(3H, m), 3.76(2H, s), 5.02(1H, dd,J=10.2, 2.7Hz), 6.70(1H, s), 7.20(2H, d, J=8.8Hz), 7.25-7.40(5H, m),7.59(2H, d, J=8.8Hz), 8.96(1H, brs), 9.21(1H, brs), 9.43(1H, brs), 10.58(1H, s) 42 mp: 205-209° C., NMR δ: 2.90-3.08(3H, m), 3.13-3.23(3H, m),4.92-4.97(1H, m), 6.20(1H, brs), 7.19-7.42(10H, m), 7.71(2H, d,J=8.8Hz), 8.76(1H, brs), 8.92(1H, brs), 9.65(1H, s) 43 NMR δ: 2.20(3H,s), 2.90-3.07(3H, m), 3.10-3.20(3H, m), 3.74(2H, s), 5.00(1H, dd, J=2.5,10.3Hz), 7.20(2H, d, J=8.8 Hz), 7.28-7.42(5H, m), 7.59(2H, d, J=8.8Hz),8.91(1H, brs), 9.13(1H, brs), 9.33(1H, brs), 10.58(1H, s) 44 NMR δ:1.48(6H, s), 2.86-3.22(6H,m ), 4.90-4.96(1H, m), 6.19(1H, brs), 6.40(1H,brs), 7.17(2H, d, J=8.8Hz), 7.27- 7.41(5H, m), 7.56(2H, d, J=8.8Hz),8.74(1H, brs), 8.90(1H, brs), 9.53(1H, brs) 45 NMR δ: 1.68-2.12(4H,m),2.43-2.59(2H, m), 2.91-3.07(3H, m), 3.11-3.20(3H, m), 3.76-3.81(1H, m),5.00(1H, d, J= 2.5, 10.3Hz), 6.20(1H, brs), 7.19(2H, d, J=8.3Hz),7.27-7.42(5H, m), 7.60(1H, d, J=8.3Hz), 8.90(1H, brs), 9.33(1H, brs),10.43(1H, s) 46 NMR δ: 2.88-3.24(6H, m), 3.83(2H, s), 4.95-5.04(1H, m),6.19(1H, brs), 7.16-7.22(2H, m), 7.26-7.45(6H, m), 7.55- 7.63(2H, m),7.87(1H, s), 8.04(1H, d, J=3.6Hz), 8.91(1H, brs), 9.32(1H, brs),10.42(1H, brs) 47 MS (m/z): 456[(M+H)⁺], NMR δ: 2.84-3.19(6H, m),4.03(2H, s), 4.87-4.97(1H, m), 5.43(2H, s), 6.12(2H, s), 7.20 (2H, d,J=8.3Hz), 7.25-7.41(11H, m), 7.53(2H, d, J=8.3Hz), 7.90(1H, s),10.38(1H, s) 48 NMR δ: 2.88-3.18(6H, m), 3.69(2H, s), 4.87-4.95(1H, m),5.36(2H, s), 6.15-6.21(1H, m), 7.18(2H, d, J=8.3Hz), 7.27- 7.41(11H, m),7.54(2H, d, J=8.3Hz), 8.57(1H, s), 8.72(1H, brs), 8.82(1H, brs),10.20(1H, s) 49 NMR δ: 2.88-3.07(3H, m), 3.11-3.21(3H, m), 3.67(2H, s),4.93-4.99(1H, m), 5.53(2H, s), 6.20(1H, d, J=3.9Hz), 7.00 (1H, s),7.13(2H, d, J=7.3Hz), 7.18(2H, d, J=8.3Hz), 7.24-7.42(8H, m), 7.49(2H,d, J=8.3Hz), 8.82(1H, brs), 9.11(1H, brs), 10.35(1H, s) 50 NMR δ:1.76-1.87(2H, m), 2.18-2.26(2H, m), 2.80-3.22(8H, m), 4.39-4.47(1H, m),4.95-5.07(1H, m), 7.15-7.22(2H, m), 7.27-7.43(5H, m), 7.54-7.63(2H, m),7.74-7.82(1H, m), 8.27(1H, d, J=7.2Hz), 8.67(1H, d, J=4.8Hz), 8.97(1H,brs), 9.47(1H, brs), 10.74(1H, brs) 51 NMR δ: 2.90-3.10(3H, m),3.10-3.20(3H, m), 4.18(2H, s), 4.96(1H, d, J=8.0Hz), 6.20(1H, brs),7.18(2H, d, J=8.6Hz), 7.20-7.60(12H, m), 7.84(1H, s), 7.97(1H, s),8.83(1H, brs), 9.17(1H, brs), 10.55(1H, s) 52 NMR δ: 1.14(6H, d,J=12.9Hz), 2.83(1H, sep, J=12.9Hz), 2.90-3.22(6H, m), 4.38(2H, s),4.97(1H, d, J=4.1Hz), 5.39 (2H, s), 6.20(1H, brs), 7.07-7.42(10H, m),7.52(2H, d, J=8.8Hz), 7.67(2H, d, J=3.9Hz), 8.84(1H, brs), 9.17(1H,brs), 10.76(1H, s) 53 NMR δ: 1.14(6H, d, J=12.9Hz), 2.83(1H, sep,J=12.9Hz), 2.90-3.22(6H,m), 4.38(2H, s), 4.97(1H, d, J=4.1Hz), 5.39 (2H,s), 6.20(1H, brs), 7.07-7.42(10H, m), 7.52(2H, d, J=8.8Hz), 7.67(2H, d,J=3.9Hz), 8.84(1H, brs), 9.17(1H, brs), 10.76(1H, s) 54 NMR δ:2.95-3.02(3H, m), 3.15(3H, brs), 4.44(2H, s), 5.10(1H, dd, J=10.3,2.5Hz), 5.58(2H, s), 6.21(1H, brs), 7.19 (2H, d, J=8.6Hz), 7.27-7.42(6H,m), 7.51(2H, d, J=8.6Hz), 7.58-7.60(1H, m), 7.69(1H, d, J=2.4Hz),7.72(1H, d, J=2.0Hz), 7.75(1H, d, J=2.0Hz), 8.96(1H, brs), 9.44(1H,brs), 10.91(1H, s) 55 NMR δ: 2.94-3.04(3H, m), 3.15(3H, brs), 3.94(2H,s), 5.01(1H, d, J=10.3Hz), 5.31(2H, s), 6.21(1H, d, J=3.9Hz), 7.01 (1H,s), 7.17-7.41(12H, m), 7.54(2H, d, J=8.3Hz), 8.98(1H, brs), 9.35(1H,brs), 10.55(1H, s) 56 NMR δ: 2.95-3.05(3H, m), 3.15(3H, brs), 4.44(2H,s), 5.01(1H, dd, J=10.3, 2.5Hz), 5.51(2H, s), 6.20(1H, brs), 7.19 (3H,d, J=8.6Hz), 7.26-7.42(7H, m), 7.50-7.54(3H, m), 7.58(1H, d, J=2.0Hz),7.73(1H, d, J=2.0Hz), 8.95(1H, brs), 9.43 (1H, brs), 10.98(1H, s) 57 NMRδ: 2.92-3.05(3H, m), 3.15(3H, brs), 4.43(2H, s), 5.01(1H, dd, J=10.2,2.6Hz), 5.65(2H, s), 7.20(2H, d, J=8.4Hz), 7.29-7.48(5H, m),7.50-7.53(3H, m), 7.70(1H, d, J=2.0Hz), 7.78(1H, d, J=2.0Hz), 7.85(1H,dt, J=8.0, 2.0Hz), 8.49 (1H, d, J=8.0Hz), 8.94(1H, brs), 9.42(1H, brs),10.86(1H, s) 58 mp: 150-152° C., NMR δ: 2.88-3.07(3H, m), 3.08(3H, m),3.95(2H, s), 5.00(1H, dd, J=2.8, 10.0Hz), 6.21(1H, s), 6.82(1H, d,J=7.6Hz), 6.91(1H, d, J=8.0Hz), 7.17-7.23(2H, m), 7.28-7.43(5H, m),7.55-7.62(2H, m), 7.82-8.04(3H, m), 8.90(1H, brs), 9.31(1H, brs),10.67(1H, brs), 14.07(1H, brs) 59 NMR δ: 2.90-3.25(6H, m), 4.95-5.04(1H,m), 5.20(1H, s), 6.22(1H, brs), 6.78(1H, s), 7.17-7.24(2H, m), 7.27-7.44(5H, m), 7.67-7.75(2H, m), 8.50-9.10(3H, br), 9.45(1H, br), 10.22(1H,brs) 60 mp: 214-216° C., NMR δ: 2.86-3.24(6H, m), 3.65(2H, s), 4.98(1H,dd, J=2.8, 10.4Hz), 6.18(1H, d, J=6.8Hz), 6.28 (1H, d, J=8.8Hz),7.16-7.22(2H, m), 7.28-7.45(6H,m), 7.53-7.59(2H, s), 8.85(1H, brs),9.18(1H, brs), 10.36(1H, brs) 61 mp: 180-182° C., NMR δ: 0.87(6H, d,J=6.8Hz), 2.05-2.15(1H, m), 2.59-3.10(3H, m), 3.10-3.20(3H, m), 4.03(2H,d, J=7.8Hz), 4.41(2H, s), 5.01(1H, d, J=8.3Hz), 6.20(1H, brs), 7.21(2H,d, J=8.3Hz), 7.29-7.42(9H, m), 7.60(2H, d, J= 8.8Hz), 7.69(1H, d,J=1.9Hz), 7.75(1H, d, J=2.0Hz) 62 mp: 226-228° C., NMR δ: 2.87-3.23(6H,m), 4.45(2H, s), 5.02(1H, dd, J=2.4, 10.0Hz), 5.55(2H, s), 6.21(1H,brs), 7.16-7.46(11H, m), 7.49-7.55(2H, m), 7.66(1H, d, J=2.0Hz),7.71(1H, d, J=2.0Hz), 8.95(1H, brs), 9.44(1H, brs), 10.93 (1H, brs),14.82(1H, brs) 63 mp: 224-225° C., NMR δ: 2.90-3.05(3H, m),3.05-3.25(3H, m), 4.46(2H, s), 5.01(1H, d, J=8.0Hz), 5.50(2H, s), 6.21(1H, brs), 7.14-7.50(11H, m), 7.54(2H, d, J=8.8Hz), 7.70-7.73(2H, m),8.93(1H, brs), 9.39(1H, brs), 10.95(1H, s) 64 mp: 205-208° C., NMR δ:2.90-3.06(3H, m), 3.10-3.21(3H, m), 4.41(2H, s), 4.99(1H, d, J=8.3Hz),5.51(2H, s), 6.21 (1H, s), 7.06-7.12(1H, m), 7.20(2H,d, J=8.3Hz),7.28-7.42(6H,m), 7.69(2H, dd, J=2.0, 8.3Hz), 8.87(1H, s), 9.26(1H, s),10.81(1H, s) 65 mp: 211-216° C., NMR δ: 3.00(3H, brs), 3.15(3H, brs),4.44(2H, s), 5.05(1H, dd, J=10.2, 1.9Hz), 5.58(2H, s), 6.22 (1H, brs),7.14-7.22(4H, m), 7.29-7.32(1H, m), 7.37-7.42(4H, m), 7.47-7.54(3H, m),7.65(1H, s), 7.69(1H, d, J=1.9Hz), 9.02(1H, brs), 9.55(1H, brs),10.97(1H, s) 66 mp: 199-201° C., NMR δ: 2.87-3.23(6H, m), 4.45(2H, s),4.95-5.04(1H, m), 5.51(2H, s), 6.20(1H, brs), 7.10-7.43 (10H, m),7.49-7.55(2H, m), 7.71(1H, d, J=2.0Hz), 7.74(1H, d, J=2.0Hz), 8.89(1H,brs), 9.30(1H, brs), 10.90(1H, brs), 14.73(1H, brs) 67 mp: 131-135° C.,NMR δ: 3.00(3H, brs), 3.16(3H, brs), 4.49(2H, s), 5.04(1H, d, J=10.0Hz),5.56(2H, s), 6.23(1H, brs), 7.20(2H, d, J=8.2Hz), 7.23-7.34(4H, m),7.37-7.42(4H,m), 7.53(2H, d, J=8.2Hz), 7.72(2H, s), 9.01(1H, brs), 9.54(1H, brs), 11.00(1H, s) 68 mp: 217-219° C., NMR δ: 2.90-3.05(3H, m),3.05-3.20(3H, m), 4.46(2H, s), 5.00(1H, d, J=8.0Hz), 5.47(2H, s), 6.21(1H, brs), 7.20(2H, d, J=8.0Hz), 7.25-7.50(7H, m), 7.50-7.60(3H, m),7.70(1H, d, J=1.9Hz), 7.71(1H, d, J=2.0Hz), 8.91(1H, brs), 9.33(1H,brs), 10.93(1H, s) 69 mp: 213-217° C., NMR δ: 2.90-3.05(3H,m),3.05-3.20(3H,m), 4.42(2H, s), 5.02(1H, dd, J=10.2, 2.4Hz), 5.62(2H, s),6.21(1H, brs), 7.20(2H, d, J=8.3Hz), 7.29-7.42(6H, m), 7.49(2H, d,J=8.3Hz), 7.51-7.60(1H, m), 7.68-7.73(2H, m), 8.95(1H, brs), 9.42(1H,brs), 10.89(1H, s) 70 mp: 212-213° C., NMR δ: 2.87-3.23(6H, m), 4.47(2H,s), 5.02(1H, dd, J=2.4, 10.0Hz), 5.53(2H, s), 6.21(1H, brs),7.16-7.23(2H, m), 7.28-7.34(1H, m), 7.36-7.43(4H, m), 7.48-7.55(2H, m),7.57-7.67(2H, m), 7.69-7.74(2H, m), 8.95 (1H, brs), 9.43(1H, brs),10.95(1H, brs), 14.86(1H, brs) 71 mp: 209-213° C., NMR δ: 2.90-3.05(3H,m), 3.05-3.20(3H, m), 4.47(2H, s), 4.98-5.01(1H, m), 5.49(2H, s), 6.21(1H, brs), 7.21(2H, d, J=8.3Hz), 7.28-7.34(1H, m), 7.36-7.44(6H,m),7.53(2H, d, J=8.8Hz), 7.71(1H, d, J=1.9Hz), 7.74 (1H, d, J=1.9Hz),8.91(1H, brs), 9.34(1H, brs), 10.97(1H, s) 72 mp: 190-193° C., NMR δ:2.90-3.08(3H, m), 3.10-3.21(3H,m ), 4.38(2H, s), 4.99(1H, dd, J=2.5,10.2Hz), 5.69(2H, s), 6.20(1H, s), 7.21(2H, d, J=8.8Hz), 7.29-7.42(5H,m), 7.48(2H, d, J=8.3Hz), 7.70(1H, d, J=1.9Hz), 7.77(1H, s), 8.88 (1H,s), 9.27(1H, s), 10.84(1H, s) 73 mp: 233-234° C., NMR δ: 2.90-3.23(6H,m), 4.47(2H, s), 5.02(1H, dd, J=2.4, 10.0Hz), 5.44(2H, s), 6.21(1H,brs), 7.12-7.23(3H, m), 7.28-7.34(1H, m), 7.36-7.44(5H, m),7.52-7.58(2H, m), 7.66-7.73(3H, m), 7.79-7.81(1H, m), 8.96 (1H, brs),9.44(1H, brs), 10.96(1H, brs), 14.79(1H, brs) 74 mp: 180-183° C., NMR δ:2.67-2.76(4H, m), 2.78-2.86(2H, m), 4.00(2H, s), 4.66(1H, dd, J=8.3,3.9Hz), 5.39(2H, s), 5.42(1H, brs), 6.57(1H, d, J=0.9Hz), 6.78(1H, s),7.03(2H, d, J=8.3Hz), 7.21-7.26(1H, m), 7.27-7.34(4H, m), 7.46- 7.50(1H,m), 7.52(2H, d, J=8.3Hz), 7.56(1H, s), 7.58(1H, s), 8.32(1H, s),10.32(1H, s) 75 mp: 210-215° C., NMR δ: 2.91-3.03(3H, m), 3.15(3H, brs),4.44(2H, s), 5.01(1H, dd, J=10.4, 2.6Hz), 5.53(2H, s), 6.21(1H, brs),7.18(2H, d, J=8.3Hz), 7.30-7.32(1H, m), 7.37-7.42(4H, m), 7.48(2H, d,J=7.49(2H, d, J=8.3Hz), 7.74(1H, d, J=2.0Hz), 7.75(1H, d, J=2.0Hz),7.79(2H, d, J=8.3Hz), 8.94(1H, brs), 9.39(1H, brs), 10.93(1H, s) 76 mp:162-165° C., NMR δ: 2.93-3.05(3H, m), 3.14(3H, brs), 4.47(2H, s),5.03(1H, dd, J=10.3, 2.5Hz), 5.62(1H, brs), 5.89(2H, s), 7.12(2H, d,J=8.3Hz), 7.30-7.37(1H, m), 7.39-7.43(6H,m), 7.61(2H, d, J=8.8Hz),7.69(1H, t, J=7.5Hz), 7.75(1H, d, J=1.9Hz), 7.83-7.86(2H, m), 7.97(1H,d, J=8.3Hz), 8.44(1H, d, J=8.3Hz), 8.99(1H, brs), 9.52(1H, brs), 10.84(1H, s) 77 NMR δ: 2.64-2.74(4H, m), 2.77-2.82(2H, m), 3.93(2H, s),4.63(1H, dd, J=7.8, 4.Hz), 5.33(2H, s), 6.80(2H, d, J=6.3 Hz), 7.14(2H,d, J=8.8Hz), 7.20-7.24(1H, m), 7.28-7.35(5H, m), 7.43(1H, d, J=7.8Hz),7.47-7.52(3H, m), 10.27(1H, s) 78 NMR δ: 2.63-2.72(4H, m), 2.75-2.81(2H,m), 3.79(2H, s), 4.62(1H, dd, J=7.8, 4.4Hz), 5.30(1H, brs), 5.33(2H, s),6.68 (1H, d, J=1.0Hz), 6.91(1H, dd, J=8.8, 5.9Hz), 7.06(1H, d, J=1.0Hz),7.12(2H, d, J=8.8Hz), 7.19-7.24(2H, m), 7.28- 7.33(4H, m), 7.43(2H, d,J=8.3Hz), 7.49(1H, dd, J=8.3, 2.5Hz), 8.32(1H, s), 10.21(1H, s) 79 NMRδ: 2.88-3.08(3H, m), 3.10-3.22(3H, m), 4.40(2H, s), 4.97(1H, d,J=8.3Hz), 5.56(2H, s), 6.20(1H, s), 7.19(2H, d, J=8.3Hz), 7.24(1H, d,J=2.5Hz), 7.30-7.60(9H, m), 7.64(1H, d, J=2.0Hz), 7.72(1H, s), 8.83(1H,s), 9.14(1H, s), 10.71 (1H, s) 80 NMR δ: 2.90-3.08(3H, m), 3.10-3.22(3H,m), 4.44(2H, s), 5.02(1H, d, J=8.8Hz), 5.59(2H, s), 6.21(1H, s),7.20(2H, d, J=8.0Hz), 7.24-7.42(7H, m), 7.50(2H, d, J=8.8Hz), 7.72(2H,d, J=6.8Hz), 8.94(1H, s), 9.42(1H, s), 10.93(1H, s) 81 NMR δ:2.87-3.23(6H,m), 3.85(3H, s), 4.30(2H, s), 4.94-5.01(1H, m), 5.55(2H,s), 6.17-6.22(1H, br), 7.14-7.23(2H, m), 7.28-7.50(9H, m), 7.57-7.64(2H,m), 7.87-7.93(2H, m), 8.83(1H, brs), 9.10(1H, brs), 10.68(1H, brs),14.86(1H, brs) 82 NMR δ: 1.30-1.64(6H, m), 2.88-3.22(8H,m),3.45-3.65(2H, m), 4.39(2H, s), 4.97(1H, d, J=9.8Hz), 5.50(2H, s), 6.21(1H, s), 7.20(2H, d, J=8.3Hz), 7.30-7.42(9H, m), 7.51(2H, d, J=8.7Hz),7.71(2H, d, J=7.8Hz), 8.81(1H, s), 9.14(1H, s), 10.77(1H, s) 83 mp:229-232° C., NMR δ: 2.90-3.00(3H, m), 3.10-3.18(3H, m), 5.00(1H, dd,J=2.8, 10.1Hz), 5.03(2H, s), 6.27(1H, t, J=2.0Hz), 7.20(2H, d, J=8.8Hz),7.29-7.42(5H, m), 7.46(1H, d, J=2.4Hz), 7.58(2H, d, J=8.8Hz), 7.77(1H,d, J=2.0Hz), 8.91(1H, s), 9.32(1H, s), 10.53(1H, s) 84 mp: 237-240° C.,NMR δ: 2.90-3.08(3H, m), 3.10-3.22(3H, m), 4.96(1H, dd, J=2.0, 10.0Hz),5.15(2H, s), 7.21(2H, d, J=8.0Hz), 7.28-7.42(5H, m), 7.56(2H, d,J=8.4Hz), 8.03(1H, s), 8.61(1H, s), 8.82(1H,s), 9.09(1H, s), 10.57(1H,s) 85 mp: 244-248° C., NMR δ: 2.90-3.06(3H, m), 3.10-3.20(3H, m),5.00(1H, d, J=7.6Hz), 5.20(2H, s), 6.20(1H, s), 7.20- 7.50(11H, m),7.59(2H, d, J=7.2Hz), 8.94(3H, s), 9.36(1H, s), 10.95(1H, s), 12.92(1H,s) 86 mp: 223-224° C., NMR δ: 2.86-3.22(6H, m), 3.49(2H, s),4.93-5.03(1H, m), 6.20(1H, d, J=4.0Hz), 7.15-7.43(9H, m), 7.55-7.62(2H,m), 7.75(1H, dt, J=1.6, 8.0Hz), 8.45-8.53(1H, m), 8.06-9.50(2H, br),10.35(1H, brs) 87 mp: 236-238° C., NMR δ: 2.86-3.23(6H, m), 3.72(2H, s),4.91-5.02(1H, m), 6.20(1H, d, J=4.0Hz), 7.15-7.22(2H, m), 7.27-7.45(6H,m), 7.53-7.62(2H, m), 7.73-7.82(1H, m), 8.40-8.60(2H, m), 8.84(1H, brs),9.16(1H, brs), 10.35-10.50 (1H, br) 88 mp: 195-198° C., NMR δ:2.86-3.22(6H, m), 3.73(2H, s), 4.93-5.04(1H, m), 6.15-6.25(1H, br),7.14-7.22(2H, m), 7.28-7.43(7H, m), 7.54-7.63(2H, m), 8.47-8.53(2H, m),9.07(2H, brs), 10.50(1H, brs) 89 mp: 202-204° C., NMR δ: 2.71-2.81(2H,m), 2.88-3.24(8H, m), 3.49(2H, s), 4.93-5.05(1H, m), 6.20(1H, brd, J=3.2Hz), 7.15-7.23(3H, m), 7.26-7.44(6H, m), 7.52-7.60(2H m), 7.69(1H, dt,J=1.6, 7.6Hz), 8.45-8.51(1H, m), 9.07(2H, brs), 10.07(1H, brs) 90 mp:220-227° C., NMR δ: 2.80-3.20(8H, m), 4.31(2H, s), 4.42(2H, t, J=8.0Hz),5.00(1H, d, J=1.0Hz), 6.21(1H, brs), 7.20-7.40(12H, m), 7.59(2H, d,J=8.6Hz), 7.65(2H, dd, J=12.9, 0.9Hz), 8.91(1H, brs), 9.34(1H, brs),10.98(1H, s) 91 mp: 158-165° C., NMR δ: 2.51-2.78(6H, m), 3.96(2H, s),4.59(1H, t, J=5.2Hz), 5.20(1H, brs), 7.13-7.32(9H, m), 7.50-7.53(4H, m),10.33(1H, s), 12.37(1H, brs) 92 mp: 216-217° C., NMR δ: 2.31(3H, s),2.86-3.24(6H, m), 3.89(2H, s), 4.92-5.07(1H, m), 6.20(1H,d, J=4.0Hz),7.12- 7.22(3H, m), 7.28-7.45(5H, m), 7.50-7.64(2H, m), 8.30(1H, d,J=4.4Hz), 8.60-9.50(2H, br), 10.32(1H, brs) 93 mp: 236-238° C., NMR δ:2.86-3.24(6H, m), 3.95(2H, s), 4.91-5.01(1H, m), 5.44(2H, s), 6.19(1H,d, J=4.4Hz), 7.15- 7.22(2H, m), 7.27-7.43(5H, m), 7.52-7.62(2H, m),8.50-8.69(3H, m), 8.83(1H, br), 9.12(1H, brs), 10.41(1H, brs) 94 NMR δ:2.90-3.10(3H, m), 3.10-3.20(3H, m), 4.38(2H, s), 4.98(1H, t, J=10.4Hz),5.44(2H, s), 6.20(1H, d, J=3.2Hz), 7.20(2H, d, J=8.4Hz), 7.30-7.45(9H,m), 7.53(2H, d, J=8.8Hz), 7.64(2H, s), 8.85(1H, brs), 9.21(1H, brs),10.79(1H, s) 95 NMR δ: 2.31(3H, s), 2.89-3.17(6H, m), 3.79(2H, s),4.98(1H, dt, J=3.2, 10.4Hz), 7.10-7.4112H, m), 10.32(1H, s) 96 NMR δ:2.27(3H, s), 2.89-3.17(6H, m), 3.79(2H, s), 4.99(1H, dt, J=3.6, 10.0Hz),7.17-7.59(12H, m), 10.31(1H, s) 97 NMR δ: 2.44(3H, s), 2.78-3.20(6H, m),3.80(2H, s), 4.97(1H, dt, J=3.2, 10.4Hz), 7.12-7.66(12H, m), 10.33(1H,s) 98 NMR δ: 1.06(3H, d, J=6.4Hz), 2.50-2.65(2H, m), 2.90-3.15(3H, m),3.83(2H, s), 4.80-4.94(1H, m), 7.10-7.18(2H, m), 7.23-7.45(7H, m),7.52-7.60(2H, m), 7.71-7.80(1H, m), 8.41-8.52(1H, m), 10.25(1H, brs) 99mp: 203-204° C., NMR δ: 1.13(3H, d, J=6.4Hz), 2.55-2.64(1H, m),3.00-3.50(4H, m), 3.84(2H, s), 4.92-5.02(1H, m), 6.20(1H, d, J=4.0Hz),7.13-7.20(2H, m), 7.24-7.46(7H, m), 7.54-7.60(2H, m), 7.73-7.80(1H, m),8.51(1H, brs), 8.67 (1H, brs), 9.13(1H, brs), 10.31(1H, brs) 100  NMR δ:1.06(3H, d, J=6.4Hz), 2.50-2.65(1H, m), 2.57-3.50(4H, m), 3.78(2H, s),4.77-4.92(1H, m), 5.25(2H, s), 6.85 (1H, s), 7.10-7.55(15H, m),10.33(1H, brs) 101  mp: 194-196° C., NMR δ: 2.88-3.25(6H, m), 3.89(2H,s), 5.20-5.26(1H, m), 6.30(1H, s), 7.17-7.48(7H, m), 7.54- 7.60(3H, m),7.81-7.88(1H, m), 8.54(1H, d, J=4.0Hz), 8.82(1H, s), 9.16(1H, s),10.35(1H, s) 102  mp: 214-215° C., NMR δ: 2.88-3.25(6H, m), 3.85(2H, s),4.96-5.02(1H, m), 6.33(1H, d, J=3.8Hz), 7.12-7.31(6H, m), 7.39-7.48(2H,m), 7.58(2H, d, J=8.3Hz), 7.74-7.80(1H, m), 8.50(1H, s), 8.82(1H, s),9.01(1H, s), 10.30(1H, s) 103  mp: 223-225° C., NMR δ: 2.88-3.06(3H, m),3.10-3.20(3H, m), 3.84(2H, s), 4.94-5.01(1H, m), 6.24(1H, d, J=4.0Hz),7.16-7.30(5H, m), 7.38-7.46(3H, m), 7.58(2H, d, J=8.8Hz), 7.76(1H, dt,J=1.6, 7.6Hz), 8.50(1H, d, J=8.8Hz), 8.83 (1H, s), 9.08(1H, s),10.31(1H, s) 104  mp: 208-210° C., NMR δ: 2.88-3.24(6H, m), 3.99(2H, s),4.90-5.10(1H, m), 6.20(1H, d, J=3.6Hz), 7.15-7.24(2H, m), 7.28-7.44(6H,m), 7.53-7.62(2H, m), 8.50-9.30(4H, m), 10.33(1H, brs) 105  mp: 234-235°C., NMR δ: 2.94-3.25(6H, m), 4.07(2H, s), 4.90-5.02(1H, m), 6.20(1H, d,J=4.0Hz), 7.16-7.23(2H, m), 7.27-7.44(5H,m), 7.53-7.65(4H, m),7.71-7.78(1H, m), 7.94-8.00(2H, m), 8.33(1H, d, J=8.0Hz), 8.50-9.25(2H,m), 10.46(1H, brs) 106  mp: 221-222° C., NMR δ: 2.90-3.25(6H, m),3.85(2H, s), 4.92-5.08(1H, m), 6.35(1H, d, J=3.6Hz), 7.14-7.23(2H, m),7.23-7.31(1H, m), 7.33-7.50(5H, m), 7.54-7.64(2H, m), 7.76(1H, dt,J=1.6, 7.6Hz), 8.43-8.55(1H, m), 8.80-9.40 (2H, br), 10.36(1H, brs) 107 mp: 204-205°0 C., NMR δ: 2.85-3.28(6H, m), 3.85(2H, s), 5.02-5.14(1H,m), 6.37(1H, d, J=4.0Hz), 7.14-7.32(3H, m), 7.365-7.46(2H, m),7.55-7.64(2H, m), 7.70-7.86(2H, m), 8.46-8.56(2H, m), 8.57-8.65(1H, m),9.13(2H, brs), 10.37 (1H, brs) 108  NMR δ: 2.63-2.67(4H, m),2.73-2.78(2H, m), 4.07(2H, s), 4.60(1H, dd, J=7.4, 4.9Hz), 5.24(1H,brs), 5.57(2H, s), 7.12- 7.23(7H, m), 7.27-7.31(4H, m), 7.37(3H, d,J=8.3Hz), 7.46(2H, d, J=8.3Hz), 7.60-7.61(1H, m), 8.31(1H, s), 10.31(1H, s) 109  NMR δ: 2.26(3H, s), 2.40(3H, s), 2.90-3.17(6H, m), 3.75(2H,s), 4.99(1H, dt, J=3.2, 6.8Hz), 6.97-7.60(11H, m), 10.35 (1H, s) 110 mp: 183-184° C., NMR δ: 1.85-2.05(2H, m), 2.53-2.65(2H, m),2.83-3.03(3H, m), 3.05-316(1H, m), 3.88(2H, s), 4.95(1H, d, J=9.6Hz),6.15(1H, brs), 7.10-7.18(2H, m), 7.22-7.43(7H, m), 7.50-7.60(2H, m),7.75(1H, dt, J=1.6, 7.2Hz), 8.45-8.53(1H, m), 8.91(2H, brs), 10.29(1H,brs) 111  mp: 225-226° C., NMR δ: 3.02-3.14(1H, m), 3.18-3.46(3H, m),3.84(2H, s), 4.22-4.35(2H, m), 4.98-5.08(1H, m), 6.21(1H, d, J=3.6Hz),6.90-6.97(2H, m), 7.23-7.44(7H, m), 7.53-7.62(2H, m), 7.76(1H, dt,J=1.6, 7.2Hz), 8.45-8.54 (1H, m), 8.80-9.50(2H, br), 10.29(1H, brs) 112 NMR δ: 1.21(6H, s), 2.85-3.23(4H, m), 3.89(2H, s), 4.90-5.00(1H, m),6.21(1H, brs), 7.11-7.19(2H, m), 7.28-7.50 (7H, m), 7.53-7.62(2H, m),7.78-7.90(1H, m), 8.45-8.60(2H, m), 9.00-9.10(1H, br), 10.35(1H, brs)113 mp: 132-133° C., NMR δ: 2.90-3.10(3H, m), 3.13-3.23(3H, m), 4.96(1H,dd, J=2.5, 10.2Hz), 7.06-7.11(1H, m), 7.21(2H, d, J=8.7Hz),7.30-7.42(5H, m), 7.47-7.53(3H, m), 7.81-7.87(1H, m), 8.29(1H, d,J=4.9Hz), 8.78(1H, s), 9.00 (1H, s), 9.88(1H, s), 10.51(1H, s)

TABLE 3 Ex. Structure  1

23

33

41

47

58

86

93

104 

The compounds shown in Tables 4 and 5 together with chemical structuralformulae can be easily manufactured by almost the same method asmentioned in the above Examples or Manufacturing Methods or by themethod to which some modifications known to the persons skilled in theart are applied. Incidentally, in some cases, there are tautomeric,geometric or optical isomers for the compounds mentioned in Tables 4 and5, and the compounds of the present invention cover each of the isolatedisomers of the above-mentioned ones or a mixture thereof.

TABLE 4

No.

1

2

3

4

5

6

7

8

9

10

11

12

TABLE 5

No. R^(2a)

13 H

14 H

15 H

16 H

17 H

18 H

19 H

20 H

21 Cl

22 Cl

What is claimed is:
 1. A compound of formula (I):

in the formula, each of the symbols means as follows: ring B is aheteroaryl group which is unsubstituted or substituted and is optionallyfused with a benzene ring; X is a bond, or a lower alkylene or analkenylene, both of which are unsubstituted or substituted with hydroxyor a lower alkyl group, or X is a carbonyl or a group represented by—NH—, and when X is a lower alkylene which is substituted with a loweralkyl group, a carbon atom of the ring B optionally bonds with the loweralkyl group so that a ring is formed; A is a lower alkylene or a grouprepresented by -lower alkylene-O—; R^(1a), R^(1b) are the same ordifferent and each is a hydrogen atom or a lower alkyl group; R² is ahydrogen atom or a halogen atom; and Z is a group represented by ═CH—;or a salt thereof.
 2. The compound of formula (I) or the salt thereofaccording to claim 1, wherein A is methylene, ethylene, or a grouprepresented by —CH₂O—.
 3. The compound of formula (I) or the saltthereof according to claim 2, wherein the ring B is a heteroaryl groupwhich is substituted with a substituent chosen from a halogen atom,lower alkyl, lower alkenyl, lower alkynyl, hydroxy, sulfanyl, halogenolower alkyl, lower alkyl-O—, lower alkyl-S—, lower alkyl-O—CO—, carboxy,sulfonyl, sulfinyl, lower alkyl-SO—, lower alkyl-SO₂—, lower alkyl-CO—,lower alkyl-CO—O—, carbamoyl, lower alkyl-NH—CO—, di-lower alkyl-N—CO—,nitro, cyano, amino, lower alkyl-NH—, di-lower alkyl-N—, aryl-loweralkyl, halogeno aryl-lower alkyl, guanidino, lower alkyl-CO—NH, andlower alkyl-SO₂—NH—.
 4. The compound of formula (I) or the salt thereofaccording to claim 3, wherein R², R^(1a) and R^(1b) are each a hydrogenatom, and Z is ═CH—.
 5. A compound of formula (Ia):

in the formula, each of the symbols means as follows: ring B is aheteroaryl group; X is a bond or a lower alkylene group; R is a hydrogenatom, a halogen atom, a lower alkyl group, amino group, an aryl loweralkyl group, or a halogeno aryl-lower alkyl group; or a salt thereof. 6.A compound:(R)-4′-[2-[(2-Hydroxy-2-phenylethyl)amino]ethyl]-2-pyridinecarboxyanilide,(R)-2-[1-(4-chlorobenzyl)-1H-imidazol-2-yl)-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]-acetanilide,(R)-2-[1-(3,4-dichlorobenzyl)-1H-tetrazol-5-yl]-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide,(R)-2-(2-aminothiazol-4-yl)-4′-[2-(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide,(R)-2-(2-benzyl-1H-1,2,4-triazol-3-yl)-4′-[2-[(2-hydroxy-2-phenylethyl)-amino]ethyl]acetanilide,(R)-2-(2-aminopyridin-6-yl)-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide,(R)-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]-2-(2-pyridyl)acetanilide,(R)-4′-[2-[(2-hydroxy-2-phenylethyl)-amino]ethyl)-2-(2-pyrazinyl)acetanilide,(R)-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl)-2-(2-pyrimidinyl)-acetanilide,or a salt of any of the foregoing.
 7. A composition comprising at leastone compound of formula (I) or the salt thereof as claimed in one ofclaims 1 through 4 in a pharmaceutically acceptable carrier.
 8. Thecomposition as claimed in claim 7, wherein the at least one compound offormula (I) or the salt thereof is present in an amount effective forthe treating of diabetes mellitus in a human or animal patient in needof such treating.
 9. The compound of formula (I) as claimed in claim 1,wherein the compound of formula (I) is an optical isomer, a hydrate, ora solvate of the compound of formula (I).
 10. A composition comprising acompound of formula (I) as claimed in claim 1 in a pharmaceuticallyacceptable carrier, wherein the compound of formula (I) is present as apolymorphic substance.
 11. A composition comprising at least onecompound of formula (I) or the salt thereof as claimed in claim 5, in apharmaceutically acceptable carrier.
 12. A composition comprising atleast one compound or the salt of any of the foregoing as claimed inclaim 6, in a pharmaceutically acceptable carrier.
 13. A method fortreating diabetes mellitus in a human or animal patient in need of suchtreatment comprising administering to the patient an amount of acompound of formula (I) as claimed in claim 1, wherein the amount is anamount effective for such treatment.
 14. A method for treating obesityin a human or animal patient in need of such treatment comprisingadministering to the patient an amount of a compound of formula (I) asclaimed in claim 1, wherein the amount is an amount effective for suchtreatment.